Amine compounds, their production and use

ABSTRACT

A compound of the formula: ##STR1## wherein Ar 1  and Ar 2  independently represent an optionally substituted aromatic group; P and Q independently represent a divalent aliphatic hydrocarbon group having at least 2 carbon atoms and optionally having either oxygen or sulfur in the carbon chain; R 1  and R 3  independently represent --CO--R, --CONH--R (R represents a hydrocarbon group or a heterocyclic group) or a hydrocarbon group; R 2  and R 4  independently represent hydrogen or an alkyl group; R 2  and R 4  independently represent hydrogen or an alkyl group; R 1  and R 2  or R 3  and R 4 , taken together with the adjacent nitrogen atom, may form a nitrogen-containing heterocyclic group; and j represents 0 or 1, or a salt thereof, has excellent GnRH-receptor antagonizing activity and is useful as a prophylactic and therapeutic agent for hormone-dependent and other diseases.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a novel amine compound or a salt thereofhaving excellent gonadotropin releasing hormone (GnRH) receptorantagonizing activity, a process for producing it, and a pharmaceuticalcomposition containing it.

GnRH, which is a decapeptide consisting of 10 amino acids, is producedin the hypothalamus. It is known that GnRH regulates secretion ofvarious hormones such as luteinizing hormone and follicle stimulatinghormone through receptors which may be present in the anterior pituitaryto thereby play a multi-pronged physiological role including inductionof ovulation. Therefore, an antagonist or an agonist that is specificand selective for these receptors would modulate secretion of theanterior pituitary hormones. Therefore, such an antagonist or agonistcan be expected to be useful for the prevention and treatment ofanterior pituitary hormone-dependent diseases.

Since 1971 when GnRH was first discovered, a large number of its analogshave been synthesized in hopes of exploiting their agonistic orantagonistic activity. For example, leuprolerin acetate is a compoundknown to have a higher affinity for GnRH receptors than native GnRH andis less liable to be metabolized than the latter.

It is known that, when administered repeatedly, leuprolerin acetate,which is 20 to 50-fold as active as native GnRH, causes a receptordown-regulation to suppress the release and production of gonadotropinin the pituitary gland and in the testis, for it decreases the responseto gonadotropin so that its testosterone producing capacity isdiminished to the castrated level. It is known that, as a consequence,the drug displays antitumoral effects in hormone-dependent neoplasticdiseases such as cancer of the prostate. In fact, leuprolerin acetate isclinically in broad use as a therapeutic drug for prostatic cancer andendometriosis, among other diseases.

However, these GnRH agonists are peptides which are poorly absorbedafter oral administration and, hence, restricted in compatible dosageform. Moreover, there are cases in which they transiently manifestagonistic activity after the beginning of use and before the expectedefficacy begins to appear, thus causing elevation of serum steroidhormone levels and transitory exacerbation of ostealgia.

Against this background, a great deal of research synthesis of GnRHantagonists which would show therapeutic efficacy and yet be free fromthe above-mentioned adverse effects has been eagerly undertaken.

2. Related Background Art

Today, as compounds having GnRH receptor antagonizing activity, a largenumber of cyclic hexapeptide derivatives (JP-A-61-191698) and bicyclicpeptide derivatives [J. Med. Chem., 36, 3265-3273, 1993], all conceivedfrom the steric structure of GnRH, have been designed and are known.However, since they all are peptides, these compounds still have thedrawbacks of poor absorption after oral administration and poor in vivostability.

Meanwhile, synthesis of non-peptide compounds having GnRH receptorantagonizing activity has also been attempted. By way of illustration, abenzazepine compound of the formula: ##STR2## [wherein R¹ represents theamino function of an amine of the formula --NR³ R⁴, 4-morpholino,##STR3## R² represents hydrogen, alkoxy, alkyl, trifluoromethyl,halogen, nitro, hydroxyl, or dialkylamino; R³ and R⁴ independentlyrepresent hydrogen, alkyl, or alkyl substituted by hydroxyl, halogen oralkoxy; m is equal to 0 or 1; n is equal to 0, 1 or 2; R⁵ representshydroxyl, alkyl, halogen, carboxyl, alkoxycarbonyl, or alkyl substitutedby hydroxyl, halogen, alkoxy or phenyl; R⁶ represents hydrogen, alkyl,carboxyl, alkoxycarbonyl, or phenyl; and R⁷ represents hydrogen, alkyl,alkoxycarbonyl, or alkyl substituted by hydroxyl, halogen, alkoxy,phenoxy or alkoxycarbonyl] is reported in JP-A-62-116514. A compound ofthe formula: ##STR4## which has LHRH (luteinizing hormone-releasinghormone) antagonizing activity is reported in Journal of MedicinalChemistry, 32, 2036-2038, 1989.

Meanwhile, it is described in JP-A-4-253970 corresponding to U.S. Pat.No. 5,393,959 that a compound of the formula: ##STR5## [wherein R₁, R₂and R₃ each represents hydrogen, hydroxyl, C₁₋₄ alkyl, C₁₋₄ alkoxy,halogen, CF₃, or methylenedioxy; R₄ represents hydrogen or C₁₋₄ alkyl; Arepresents a bond or C₁₋₆ alkylene or alkylidene; B is C₁₋₆ alkylene oralkylidene when Y is a bond, or B is C₂₋₆ alkylene when Y is O, S or NR⁵; X represents CH or N; R₅ represents hydrogen or C₁₋₄ alkyl] hasintracellular calcium antagonizing activity and can be used as atherapeutic drug for angina pectoris and myocardial infarction.

Furthermore, Journal of Medicinal Chemistry, 34, 12-19 (1991) mentionsthat a compound of the formula: ##STR6## [wherein Ar¹ and Ar² eachrepresents H, phenyl, or 2-, 3- or 4-pyridyl; Am represents2,6-dimethyl-1-piperidinyl, 1-piperidinyl, or2,5-dimethyl-1-pyrrolidinyl; n is equal to 1-4; X represents OH, H,cyano, aminomethyl, acetolaminomethyl or carbamoyl] has antiarrhythmicactivity. Archives of International Pharmacodynamics, 107, 194-201, 1956describes that a compound of the formula: ##STR7## [wherein R represents--CONH₂, --NH₂, --NHCOCH₃, --NHCOC₆ H₅, --CH₂ NH₂, --CH₂ NHCOCH₃, --CH₂NHCOC₆ H₅ or --CN; NAA' represents N(CH₃)₂, N(C₂ H₅)₂, N(i--C₃ H₇)₂, NC₄H₈, NC₅ H₁₀ or NC₄ H₈ O] has parasympathomimetic activity.

JP-A-62-123164 mentions that a compound of the formula: ##STR8##[wherein X and Y, which may be the same or different, are selected fromthe class consisting of phenyl groups which may respectively besubstituted by 1 or 2 substituents selected from among halogen, CF₃, OHand C₁₋₄ alkoxy; R¹ and R² are the same or different and each isselected from the class consisting of lower alkyl groups of 1-4 carbonatoms, or R¹ and R², taken together with the nitrogen atom, form asaturated 5- or 6-membered ring; R³ and R⁴ are selected from amonghydrogen, lower alkyl or alkenyl of 1-6 carbon atoms, cyclopentyl andcyclohexyl; n is equal to 0 or 1] has antitumoral activity.

However, a non-peptide compound having sufficiently high GnRH receptorantagonizing activity for use as a medicine has not been discovered.Therefore, an aromatic amine derivative structurally different from theabove-mentioned known compounds and having GnRH receptor antagonizingactivity with a high clinical potential and safety has been awaited inearnest.

SUMMARY OF THE INVENTION

An object of the present invention is to provide a compound of theformula: ##STR9## wherein Ar¹ and Ar² independently represent anoptionally substituted aromatic group;

P and Q independently represent a divalent aliphatic hydrocarbon grouphaving at least 2 carbon atoms, which may have either oxygen or sulfurwithin the carbon chain;

R¹ and R³ independently represent i) an acyl group of --CO--R or--CONH--R wherein R represents an optionally substituted hydrocarbongroup or an optionally substituted heterocyclic group, or ii) anoptionally substituted hydrocarbon group;

R² and R⁴ independently represent hydrogen or an optionally substitutedalkyl group;

R¹ and R² or R³ and R⁴, taken together with the adjacent nitrogen atom,may form an optionally substituted nitrogen-containing heterocyclicgroup; and

j represents 0 or 1, or a salt thereof.

A further object of the invention is to provide a gonadotropin-releasinghormone receptor antagonistic composition which comprises a compound ofthe formula: ##STR10## wherein Ar¹ and Ar² independently represent anoptionally substituted aromatic group;

P^(a) and Q^(a) independently represent a divalent aliphatic hydrocarbongroup which may have either oxygen or sulfur within the carbon chain;

R^(1a) and R^(3a) independently represent an acyl group or an optionallysubstituted hydrocarbon group;

R² and R⁴ independently represent hydrogen or an optionally substitutedalkyl group;

R^(1a) and R² or R^(3a) and R⁴, taken together with the adjacentnitrogen atom, may form an optionally substituted nitrogen-containingheterocyclic group; and

j represents 0 or 1, or a salt thereof, and

a pharmaceutically acceptable carrier.

A further object of the invention is to provide a method for treatingdiseases related to gonadotropin-releasing hormone in mammals whichcomprises the steps of selecting a compound of the formula: ##STR11##wherein Ar¹ and Ar² independently represent an optionally substitutedaromatic group;

P^(a) and Q^(a) independently represent a divalent aliphatic hydrocarbongroup which may have either oxygen or sulfur within the carbon chain;

R^(1a) and R^(3a) independently represent an acyl group or an optionallysubstituted hydrocarbon group;

R² and R⁴ independently represent hydrogen or an optionally substitutedalkyl group;

R^(1a) and R² or R^(3a) and R⁴, taken together with the adjacentnitrogen atom, may form an optionally substituted nitrogen-containingheterocyclic group; and

j represents 0 or 1, or a salt thereof, and

administering to a subject a therapeutically effective amount of saidcompound.

A further object of the invention is to provide a method ofmanufacturing a pharmaceutical composition for treating diseases relatedto gonadotropin-releasing hormone, comprising the steps of selecting acompound of the formula: ##STR12## wherein Ar¹ and Ar² independentlyrepresent an optionally substituted aromatic group;

P^(a) and Q^(a) independently represent a divalent aliphatic hydrocarbongroup which may have either oxygen or sulfur within the carbon chain;

R^(1a) and R^(3a) independently represent an acyl group or an optionallysubstituted hydrocarbon group;

R² and R⁴ independently represent hydrogen or an optionally substitutedalkyl group;

R^(1a) and R² or R^(3a) and R⁴, taken together with the adjacentnitrogen atom, may form an optionally substituted nitrogen-containingheterocyclic group; and

j represents 0 or 1, or a salt thereof, and

admixing said compound with a pharmaceutically acceptable carrier.

The inventors discovered a non-peptide compound activity, Compound (I)or Compound (I'), of the formula: ##STR13## wherein Ar¹ and Ar²independently represent an optionally substituted aromatic group;

P and Q independently represent a divalent aliphatic hydrocarbon grouphaving at least 2 carbon atoms, which may have either oxygen or sulfurwithin the carbon chain;

R¹ and R³ independently represent i) an acyl group of --CO--R or--CONH--R wherein R represents an optionally substituted hydrocarbongroup or an optionally substituted heterocyclic group, or ii) anoptionally substituted hydrocarbon group;

R² and R⁴ independently represent hydrogen or an optionally substitutedalkyl group;

R¹ and R² or R³ and R⁴, taken together with the adjacent nitrogen atom,may form an optionally substituted nitrogen-containing heterocyclicgroup; and

j represents 0 or 1, [Compound (I)] or a salt thereof, and the compoundof the formula: ##STR14## wherein P^(a) and Q^(a) independentlyrepresent a divalent aliphatic hydrocarbon group which may have eitheroxygen or sulfur within the carbon chain;

R^(1a) and R^(3a) independently represent an acyl group or an optionallysubstituted hydrocarbon group;

R^(1a) and R² or R^(3a) and R⁴, taken together with the adjacentnitrogen atom, may form an optionally substituted nitrogen-containingheterocyclic group; and the other symbols are defined as above,[Compound (I')]. The compounds of the invention or a salt thereof,exhibit excellent GnRH receptor antagonizing activity and low toxicitywithout being materially influenced by the presence or absence or kindsof substituents on the rings, thus being of great clinical use.

DETAILED DESCRIPTION OF THE INVENTION

This invention is, therefore, directed to:

(1) a compound (I) or a salt thereof,

(2) a process for producing compound (1), which comprises reacting acompound of the formula: ##STR15## wherein all symbols have the samemeanings as defined above, or a salt thereof, with a compound of theformula:

    R.sup.4 --L

wherein L represents a leaving group and R⁴ is as defined above or asalt thereof, and

(3) a gonadotropin-releasing hormone receptor antagonistic compositionwhich comprises a compound (I') or a salt thereof.

In a compound (1), preferably, Ar¹ and Ar² are independently C₆₋₁₄ arylgroup which may be substituted by 1 to 5 substituents selected from thegroup consisting of halogen, C₁₋₃ alkylenedioxy, nitro, cyano,optionally halogenated C₁₋₆ alkyl, optionally halogenated C₃₋₆cycloalkyl, optionally halogenated C₁₋₆ alkoxy, optionally halogenatedC₁₋₆ alkylthio, hydroxyl, amino, mono-C₁₋₆ alkylamino, di-C₁₋₆alkylamino, C₁₋₆ alkyl-carbonylamino, C₁₋₆ alkyl-carbonyl, carboxyl,C₁₋₆ alkoxy-carbonyl, carbamoyl, mono-C₁₋₆ alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, sulfo, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₀aryl and C₆₋₁₀ aryloxy,

P and Q are independently divalent C₂₋₆ aliphatic hydrocarbon groupwhich may have either oxygen or sulfur within the carbon chain,

R¹ and R³ are independently i) an acyl group of --CO--R^(a) or--CONH--R^(a) wherein R^(a) is a) a C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₄ aryl or C₇₋₁₆ aralkyl group which may besubstituted by 1 to 5 substituents selected from the group consisting ofhalogen, C₁₋₃ alkylenedioxy, nitro, cyano, optionally halogenated C₁₋₆alkyl, optionally halogenated C₃₋₆ cycloalkyl, optionally halogenatedC₁₋₆ alkoxy, optionally halogenated C₁₋₆ alkylthio, hydroxyl, amino,mono-C₁₋₆ alkylamino, di-C₁₋₆ alkylamino, C₁₋₆ alkyl-carbonylamino, C₁₋₆alkyl-carbonyl, carboxyl, C₁₋₆ alkoxy-carbonyl, carbamoyl, mono-C₁₋₆alkylcarbamoyl, di-C₁₋₆ alkylcarbamoyl, sulfo, C₁₋₆ alkylsulfonyl, C₁₋₆alkylsulfinyl, and 5- or 6-membered heterocyclic group, or b) a 5- to10-membered heterocyclic group containing, besides carbon atom, 1 to 4hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom,which may be substituted by 1 to 5 substituents selected from the groupconsisting of halogen, C₁₋₃ alkylenedioxy, nitro, cyano, optionallyhalogenated C₁₋₆ alkyl, optionally halogenated C₃₋₆ cycloalkyl,optionally halogenated C₁₋₆ alkoxy, optionally halogenated C₁₋₆alkylthio, hydroxyl, amino, mono-C₁₋₆ alkylamino, di-C₁₋₆ alkylamino,C₁₋₆ alkyl-carbonylamino, C₁₋₆ alkyl-carbonyl, carboxyl, C₁₋₆alkoxy-carbonyl, carbamoyl, mono-C₁₋₆ alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, sulfo, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₀aryl and C₆₋₁₀ aryloxy, or ii) a C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₆ cycloalkyl, C₆₋₁₄ aryl or C₇₋₁₆ aralkyl group which may besubstituted by 1 to 5 substituents selected from the group consisting ofhalogen, C₁₋₃ alkylenedioxy, nitro, cyano, optionally halogenated C₁₋₆alkyl, optionally halogenated C₃₋₆ cycloalkyl, optionally halogenatedC₁₋₆ alkoxy, optionally halogenated C₁₋₆ alkylthio, hydroxyl, amino,mono-C₁₋₆ alkylamino, di-C₁₋₆ alkylamino, C₁₋₆ alkyl-carbonylamino, C₁₋₆alkyl-carbonyl, carboxyl, C₁₋₆ alkoxy-carbonyl, carbamoyl, mono-C₁₋₆alkylcarbamoyl, di-C₁₋₆ alkylcarbamoyl, sulfo, C₁₋₆ alkylsulfonyl, C₁₋₆alkylsulfinyl and 5- or 6-membered heterocyclic group, and

R² and R⁴ are independently hydrogen or a C₁₋₆ alkyl group which may besubstituted by 1 to 5 substituents selected from the group consisting ofhalogen, nitro, cyano, optionally halogenated C₃₋₆ cycloalkyl,optionally halogenated C₁₋₆ alkoxy, optionally halogenated C₁₋₆alkylthio, hydroxyl, amino, mono-C₁₋₆ alkylamino, di-C₁₋₆ alkylamino,C₁₋₆ alkyl-carbonylamino, C₁₋₆ alkyl-carbonyl, carboxyl, C₁₋₆alkoxy-carbonyl, carbamoyl, mono-C₁₋₆ alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, sulfo, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₀aryl and C₆₋₁₀ aryloxy, or

R¹ and R² or R³ and R⁴, taken together with the adjacent nitrogen atom,form a nitrogen-containing heterocyclic group of the formula: ##STR16##wherein ring A is a 4- to 8-membered ring which may be substituted byhydroxyl or oxo group; and V is >O, >C═O, ##STR17## or >N--W in which Wis a) hydrogen, b) a C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆cycloalkyl, C₆₋₁₄ aryl or C₇₋₁₆ aralkyl group which may be substitutedby 1 to 5 substituents selected from the group consisting of halogen,C₁₋₃ alkylenedioxy, nitro, cyano, optionally halogenated C₁₋₆ alkyl,optionally halogenated C₃₋₆ cycloalkyl, optionally halogenated C₁₋₆alkoxy, optionally halogenated C₁₋₆ alkylthio, hydroxyl, amino,mono-C₁₋₆ alkylamino, di-C₁₋₆ alkylamino, C₁₋₆ alkyl-carbonylamino, C₁₋₆alkyl-carbonyl, carboxyl, C₁₋₆ alkoxy-carbonyl, carbamoyl, mono-C₁₋₆alkylcarbamoyl, di-C₁₋₆ alkylcarbamoyl, sulfo, C₁₋₆ alkylsulfonyl, C₁₋₆alkylsulfinyl and 5- or 6-membered heterocyclic group, or c) a 5- to10-membered heterocyclic group containing, besides carbon atom, 1 to 4hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom,which may be substituted by 1 to 5 substituents selected from the groupconsisting of halogen, C₁₋₃ alkylenedioxy, nitro, cyano, optionallyhalogenated C₁₋₆ alkyl, optionally halogenated C₃₋₆ cycloalkyl,optionally halogenated C₁₋₆ alkoxy, optionally halogenated C₁₋₆alkylthio, hydroxyl, amino, mono-C₁₋₆ alkylamino, di-C₁₋₆ alkylamino,C₁₋₆ alkyl-carbonylamino, C₁₋₆ alkyl-carbonyl, carboxyl, C₁₋₆alkoxy-carbonyl, carbamoyl, mono-C₁₋₆ alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, sulfo, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₀aryl and C₆₋₁₀ aryloxy, and W^(a) is hydrogen or hydroxyl, ##STR18##wherein ring B is a 4- to 12-membered mono- or bicyclic ring optionallyhaving an oxo group and optionally substituted by 1 to 5 C₁₋₆ alkylgroups; and

ring D is a 4- to 12-membered aromatic ring which may be substituted by1 to 5 substituents selected from the group consisting of halogen, C₁₋₃alkylenedioxy, nitro, cyano, optionally halogenated C₁₋₆ alkyl,optionally halogenated C₃₋₆ cycloalkyl, optionally halogenated C₁₋₆alkoxy, optionally halogenated C₁₋₆ alkylthio, hydroxyl, amino,mono-C₁₋₆ alkylamino, di-C₁₋₆ alkylamino, C₁₋₆ alkyl-carbonylamino, C₁₋₆alkyl-carbonyl, carboxyl, C₁₋₆ alkoxy-carbonyl, carbamoyl, mono-C₁₋₆alkylcarbamoyl, di-C₁₋₆ alkylcarbamoyl, sulfo, C₁₋₆ alkylsulfonyl, C₁₋₆alkylsulfinyl, C₆₋₁₀ aryl and C₆₋₁₀ aryloxy, or ##STR19## wherein ring Eis a 5- to 10-membered aromatic ring which may be substituted by 1 to 5substituents selected from the group consisting of halogen, C₁₋₃alkylenedioxy, nitro, cyano, optionally halogenated C₁₋₆ alkyl,optionally halogenated C₃₋₆ cycloalkyl, optionally halogenated C₁₋₆alkoxy, optionally halogenated C₁₋₆ alkylthio, hydroxyl, amino,mono-C₁₋₆ alkylamino, di-C₁₋₆ alkylamino, C₁₋₆ alkyl-carbonylamino, C₁₋₆alkyl-carbonyl, carboxyl, C₁₋₆ alkoxy-carbonyl, carbamoyl, mono-C₁₋₆alkylcarbamoyl, di-C₁₋₆ alkylcarbamoyl, sulfo, C₁₋₆ alkylsulfonyl, C₁₋₆alkylsulfinyl, C₆₋₁₀ aryl and C₆₋₁₀ aryloxy;

X is --CH₂ --, --CO-- or --CH(OH)--;

Y is --CH₂ --, --O-- or --NW^(b) -- in which W^(b) is hydrogen or a C₁₋₆alkyl group which may be substituted by 1 to 5 substituents selectedfrom the group consisting of halogen, C₁₋₃ alkylenedioxy, nitro, cyano,optionally halogenated C₃₋₆ cycloalkyl, optionally halogenated C₁₋₆alkoxy, optionally halogenated C₁₋₆ alkylthio, hydroxyl, amino,mono-C₁₋₆ alkylamino, di-C₁₋₆ alkylamino, C₁₋₆ alkyl-carbonylamino, C₁₋₆alkyl-carbonyl, carboxyl, C₁₋₆ alkoxy-carbonyl, carbamoyl, mono-C₁₋₆alkylcarbamoyl, di-C₁₋₆ alkylcarbamoyl, sulfo, C₁₋₆ alkylsulfonyl, C₁₋₆alkylsulfinyl, C₆₋₁₀ aryl, C₆₋₁₀ aryloxy and 5- or 6-memberedheterocyclic group;

k+m is an integer of 1 to 4; and

n is an integer of 1 to 3.

In a compound (I), R¹ is preferably a C₇₋₁₆ aralkyl, C₃₋₆ cycloalkyl orbenzo-C₃₋₆ cycloalkyl group which may be substituted by 1 to 5substituents selected from the group consisting of halogen, optionallyhalogenated C₁₋₆ alkyl, optionally halogenated C₁₋₆ alkoxy and C₁₋₆alkoxy-carbonyl.

In a compound (I), R³ is preferably an acyl group of --CO--R^(b) whereinR^(b) is a C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,C₆₋₁₄ aryl or C₇₋₁₆ aralkyl group which may be substituted by 1 to 5substituents selected from the group consisting of halogen, C₁₋₃alkylenedioxy, nitro, cyano, optionally halogenated C₃₋₆ cycloalkyl,optionally halogenated C₁₋₆ alkoxy, optionally halogenated C₁₋₆alkylthio, hydroxyl, amino, mono-C₁₋₆ alkylamino, di-C₁₋₆ alkylamino,C₁₋₆ alkyl-carbonylamino, C₁₋₆ alkyl-carbonyl, carboxyl, C₁₋₆alkoxy-carbonyl, carbamoyl, mono-C₁₋₆ alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, sulfo, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl and 5- or6-membered heterocyclic group.

In a compound (I), ##STR20## is preferably the formula: ##STR21##wherein ring E^(a) is a benzene ring which may be substituted by 1 to 4substituents selected from the group consisting of halogen, C₁₋₃alkylenedioxy, nitro, cyano, optionally halogenated C₁₋₆ alkyl,optionally halogenated C₃₋₆ cycloalkyl, optionally halogenated C₁₋₆alkoxy, optionally halogenated C₁₋₆ alkylthio, hydroxyl, amino,mono-C₁₋₆ alkylamino, di-C₁₋₆ alkylamino, C₁₋₆ alkyl-carbonylamino, C₁₋₆alkyl-carbonyl, carboxyl, C₁₋₆ alkoxy-carbonyl, carbamoyl, mono-C₁₋₆alkylcarbamoyl, di-C₁₋₆ alkylcarbamoyl, sulfo, C₁₋₆ alkylsulfonyl, C₁₋₆alkylsulfinyl, C₆₋₁₀ aryl and C₆₋₁₀ aryloxy.

In a compound (1), P and Q are preferably independently a C₂₋₆ alkyleneor C₂₋₆ alkenylene group.

In a compound (1), P and Q are preferably independently a C₃₋₅ alkylenegroup.

In a compound (1), R⁴ is preferably hydrogen.

In a compound (1), j is preferably O.

In a compound (1), preferable is the compound of the formula: ##STR22##wherein Ar³ and Ar⁴ are independently an optionally halogenated phenylgroup; Alk₁ and Alk₂ are independently a C₂₋₆ alkylene group; Ar⁵ is aC₇₋₁₆ aralkyl group which may be substituted by halogen or optionallyhalogenated C₁₋₃ alkoxy; and ring E^(a) is a benzene ring which may besubstituted by 1 to 3 substituents selected from the group consisting ofoptionally halogenated C₁₋₃ alkoxy, C₁₋₃ alkyl-carbonyl and amino.

In a compound (1), more preferable is

(+)-3,4-Dihydro-6-methoxy-1'-{4,4-diphenyl-7-{[(4-methoxyphenyl)acetyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine],

(-)-3,4-Dihydro-6-methoxy-1'-{4,4-diphenyl-7-{[(4-methoxyphenyl)acetyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine],

(-)-3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-{[(4-methoxyphenyl)acetyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine]-1-one,

(-)-3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-{[(4-fluorophenyl)acetyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine],

(+)-3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-{[(4-fluorophenyl)acetyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine],

(-)-3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-{[3-(4-fluorophenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine],

(+)-3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-{[3-(4-fluorophenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine],

(+)-3,4-Dihydro-6,7-dimethoxy-1'-{7-{[3-(4-chlorophenyl)propionyl]amino}-4,4-diphenylheptyl}spiro[naphthalene-2(1H),2'-piperidine],

(-)-3,4-Dihydro-6,7-dimethoxy-1'-{7-{[3-(4-chlorophenyl)propionyl]amino}-4,4-diphenylheptyl}spiro[naphthalene-2(1H),2'-piperidine],

(-)-3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-{[3-(4-methoxyphenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine],

(+)-3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-{[3-(4-methoxyphenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine],

3,4-Dihydro-4'-{4,4-diphenyl-7-{[3-(4-methoxyphenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),3'-morpholine],

3,4-Dihydro-7-methoxy-4'-{4,4-diphenyl-7-{[3-(4-methoxyphenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),3'-morpholine],

3,4-Dihydro-6,7-dimethoxy-4'-{4,4-diphenyl-7-{[3-(4-methoxyphenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),3'-morpholine],or a salt thereof.

In a composition (3), preferred is composition for treating a sexhormone-dependent disease.

In a composition (3), more preferred is a composition for treatingtumor, prostatic hypertrophy, endometriosis, precocious puberty orpremenstrual syndrome.

The aromatic group of the "optionally substituted aromatic group" forAr¹ and Ar² includes, for example, aromatic hydrocarbon groups andheteroaromatic groups. Preferred is an aromatic hydrocarbon group.

The "aromatic hydrocarbon group" mentioned above includes, for example,monocyclic or fused polycyclic aromatic hydrocarbon groups of 6 to 14carbon atoms. Thus, C₆₋₁₄ aryl groups such as phenyl, 1-naphthyl,2-naphthyl, indenyl, anthryl, etc. can be mentioned, among other groups.Particularly preferred is phenyl in many instances.

The "heteroaromatic group" mentioned above includes, for example, 5- to14-membered monocyclic, bicyclic or tricyclic heteroaromatic groupscontaining 1 or 2 kinds of and preferably 1 to 3 hetero atoms selectedfrom among nitrogen, oxygen and sulfur in addition to carbon as ringmembers. Thus, 5- to 10-membered (monocyclic or bicyclic) heteroaromaticgroups containing 1-3 hetero atoms selected from among nitrogen, oxygenand sulfur in addition to carbon as ring members, such as 2-thienyl,3-thienyl, 2-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 4-quinolyl,8-quinolyl, 4-isoquinolyl, pyrazinyl, 2-pyrimidinyl, 3-pyrrolyl,2-imidazolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, 1-indolyl,2-isoindolyl, etc. can be mentioned.

Particularly preferred in many instances are 5- or 6-memberedheteroaromatic groups containing 1-3 hetero atoms selected from amongnitrogen, oxygen and sulfur in addition to carbon as ring members (e.g.2-pyridyl, 4-pyridyl, etc.).

The substituent that may be present on the "optionally substitutedaromatic group" for Ar¹ and Ar² includes, for example, halogen (e.g.fluorine, chlorine, bromine, iodine), C₁₋₃ alkylenedioxy (e.g.methylenedioxy, ethylenedioxy, etc), nitro, cyano, optionallyhalogenated C₁₋₆ alkyl, optionally halogenated C₃₋₆ cycloalkyl,optionally halogenated C₁₋₆ alkoxy, optionally halogenated C₁₋₆alkylthio, hydroxyl, amino, mono-C₁₋₆ alkylamino (e.g. methylamino,ethylamino, etc.), di-C₁₋₆ alkylamino (e.g. dimethylamino, diethylamino,etc.), C₁₋₆ alkyl-carbonylamino (e.g. methylcarbonylamino,ethylcarbonylamino, etc.), C₁₋₆ alkyl-carbonyl (e.g. acetyl,ethylcarbonyl, etc.), carboxyl, C₁₋₆ alkoxy-carbonyl (e.g.methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.),carbamoyl, mono-C₁₋₆ alkylcarbamoyl (e.g. methylcarbamoyl,ethylcarbamoyl, etc.), di-C₁₋₆ alkylcarbamoyl (e.g. dimethylcarbamoyl,diethylcarbamoyl, etc.), sulfo, C₁₋₆ alkylsulfonyl (e.g methylsulfonyl,ethylsulfonyl, etc.), C₁₋₆ alkylsulfinyl (e.g. methylsulfinyl,ethylsulfinyl, etc.), C₆₋₁₀ aryl (e.g. phenyl, etc.) and C₆₋₁₀ aryloxy(e.g. phenyloxy, etc.)

The aromatic group of the "optionally substituted aromatic group" mayhave 1 to 5, preferably 1 to 3, suitable substituent groups selectedfrom among those mentioned above in substitutable positions of the ringstructure, and where the number of such substituents is 2 or more, thesubstituent groups may be the same or different.

The "optionally halogenated C₁₋₆ alkyl" as the term is used in thisspecification includes, for example, C₁₋₆ alkyl groups optionally having1-3 halogen atoms (e.g. F, Cl, Br, I) (e.g. methyl, chloromethyl,difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl,2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl,isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl,6,6,6-trifluorohexyl, etc.).

The "optionally halogenated C₃₋₆ cycloalkyl" as the term is used in thisspecification includes, for example, C₃₋₆ cycloalkyl groups optionallyhaving 1-3 halogen atoms (e.g. F, Cl, Br, I) (e.g. cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, 2,2,3,3-tetrafluorocyclopentyl,4-chlorocyclohexyl, etc.).

The "optionally halogenated C₁₋₆ alkoxy" as the term is used in thisspecification includes, for exmaple, C₁₋₆ alkoxy groups optionallyhaving 1-3 halogen atoms (e.g. F, Cl, Br, I) (e.g. methoxy,difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy,propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy,sec-butoxy, pentyloxy, hexyloxy, etc.).

The "optionally halogenated C₁₋₆ alkylthio" as the term is used in thisspecification includes, for example, C₁₋₆ alkylthio groups optionallyhaving 1-3 halogen atoms (e.g. F, Cl, Br, I) (for example, methylthio,difluoromethylthio, trifluoromethylthio, ethylthio, propylthio,isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio,hexylthio, etc.).

The hydrocarbon group of the "optionally substituted hydrocarbon group"as the term is used for R, R¹ and R³ in this specification includesgroups available upon elimination of one hydrogen atom each fromhydrocarbon compounds, such as alkyl, alkenyl, cycloalkyl, aryl, aralkyland other groups. Preferred are acyclic or cyclic hydrocarbon groups of1-16 carbon atoms such as the following.

a) C₁₋₆ alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl, etc.)

b) C₂₋₆ alkenyl (e.g. vinyl, allyl, isopropenyl, butenyl, isobutenyl,sec-butenyl, etc.)

c) C₂₋₆ alkynyl (e.g. propargyl, ethynyl, butynyl, 1-hexynyl, etc.)

d) optionally halogenated C₃₋₆ cycloalkyl; cyclohexyl may be fused to abenzene ring which may have 1-3 C₁₋₆ alkoxy (e.g. methoxy) groups.

e) C₆₋₁₄ aryl (e.g. phenyl, tolyl, xylyl, 1-naphthyl, 2-naphthyl,biphenyl, 2-indenyl, 2-anthryl, etc.); C₆₋₁₀ aryl (e.g. phenyl, etc.) inparticular.

f) C₇₋₁₆ aralkyl (e.g. benzyl, phenethyl, diphenylmethyl,triphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-diphenylethyl,3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, etc.); benzyl inparticular.

The substituent which may be present on the "optionally substitutedhydrocarbon group" for R, R¹ and R³ includes, for example, halogen (e.g.fluorine, chlorine, bromine, iodine), C₁₋₃ alkylenedioxy (e.g.methylenedioxy, ethylenedioxy, etc), nitro, cyano, optionallyhalogenated C₁₋₆ alkyl, optionally halogenated C₃₋₆ cycloalkyl,optionally halogenated C₁₋₆ alkoxy, optionally halogenated C₁₋₆alkylthio, hydroxyl, amino, mono-C₁₋₆ alkylamino (e.g. methylamino,ethylamino, etc.), di-C₁₋₆ alkylamino (e.g. dimethylamino, diethylamino,etc.), C₁₋₆ alkyl-carbonylamino (e.g. methylcarbonylamino,ethylcarbonylamino, etc.), C₁₋₆ alkyl-carbonyl (e.g. acetyl,ethylcarbonyl, etc.), carboxyl, C₁₋₆ alkoxy-carbonyl (e.g.methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.),carbamoyl, mono-C₁₋₆ alkylcarbamoyl (e.g. methylcarbamoyl,ethylcarbamoyl, etc.), di-C₁₋₆ alkylcarbamoyl (e.g. dimethylcarbamoyl,diethylcarbamoyl, etc.), sulfo, C₁₋₆ alkylsulfonyl (e.g. methylsulfonyl,ethylsulfonyl, etc.), C₁₋₆ alkylsulfinyl (e.g. methylsulfinyl,ethylsulfinyl, etc.), C₆₋₁₀ aryl (e.g. phenyl, etc.), C₆₋₁₀ aryloxy(e.g. phenyloxy, etc.), 5- or 6-membered heterocyclic groups (e.g. ringscontaining 1-3 hetero atoms selected from among N, O and S in additionto C as ring members, such as 1-, 2- or 3-pyrrolidinyl, 2- or4-imidazolidinyl, 2-, 3- or 4-pyrazolidinyl, 1-, 2-, 3- or 4-piperidyl,1- or 2-piperazinyl, morpholinyl, 2-thienyl, 3-thienyl, 2-pyridyl,4-pyridyl, 2-furyl, 3-furyl, pyrazinyl, 2-pyrimidinyl, 3-pyrrolyl,2-imidazolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, etc.).

The hydrocarbon group of the "optionally substituted hydrocarbon group"may have 1-5, preferably 1-3, suitable substituents such as thosementioned above in substitutable positions, and where the number ofsubstituents is 2 or more, the substituent groups may be the same ordifferent.

The heterocyclic group of the "optionally substituted heterocyclicgroup" for R includes, for example, 5- to 10-membered (monocyclic orbicyclic) heterocyclic groups containing 1 to 3 hetero atoms of one ortwo kinds selected from among nitrogen, oxygen and sulfur in addition tocarbon as ring members (e.g. non-aromatic heterocyclic groups such as1-, 2- or 3-pyrrolidinyl, 2- or 4-imidazolidinyl, 2-, 3- or4-pyrazolidinyl, 1-, 2-, 3- or 4-piperidyl, 1- or 2-piperazinyl,morpholinyl, etc. and aromatic heterocyclic (heteroaromatic) groups suchas 2-thienyl, 3-thienyl, 2-pyridyl, 4-pyridyl, 2-furyl, 3-furyl,4-quinolyl, 8-quinolyl, 4-isoquinolyl, pyrazinyl, 2-pyrimidinyl,3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl,1-indolyl, 2-isoindolyl, etc.). Preferred are "heteroaromatic groupsthat may have a substituent or substituents". Thus, for example, 5- to10-membered (monocyclic or bicyclic) heteroaromatic groups containing1-3 hetero atoms of one or two kinds selected from among N, O and S inaddition to C as ring members (e.g. 2-thienyl, 3-thienyl, 2-pyridyl,4-pyridyl, 2-furyl, 3-furyl, 4-quinolyl, 8-quinolyl, 4-isoquinolyl,pyrazinyl, 2-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl,3-isothiazolyl, 3-isoxazolyl, 1-indolyl, 2-isoindolyl, etc.) arepreferred in many instances. Particularly, 5- or 6-memberedheteroaromatic groups containing 1-3 hetero atoms selected from among N,O and S in addition to C (e.g. 2-thienyl, 3-thienyl, 2-pyridyl,4-pyridyl, etc.) are selected in many instances.

The substituent that may be present on the heterocyclic group of the"optionally substituted heterocyclic group" typically includes thesubstituents mentioned for the optionally substituted aromatic group forAr¹ and Ar².

The alkyl group for the "optionally substituted alkyl" for R² and R⁴includes, for example, straight-chain or branched lower(C₁₋₆)alkylgroups (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl, etc.).

The substituent which may be present on the "alkyl" may for example beany of the substituent groups mentioned for the "optionally substitutedhydrocarbon group" for R, R¹ and R³, and C₆₋₁₀ aryl groups (e.g. phenyletc).

The divalent aliphatic hydrocarbon group of at least 2 carbon atoms ofthe "divalent aliphatic hydrocarbon group containing at least 2 carbonatoms, which may have either oxygen or sulfur within the carbon chain"for P and Q includes a divalent group of at least 2 carbon atoms whichis available on elimination of hydrogen atoms from the same or differentcarbon atoms of saturated or unsaturated aliphatic hydrocarbon and ispreferably a hydrocarbon group containing 6 or fewer carbon atoms. Moreparticularly, examples of the hydrocarbon group include:

(i) alkylene groups (e.g. ##STR23## (ii) alkenylene groups (e.g.##STR24## (iii) alkynylene groups (e.g. --C≡C--, --CH₂ --C≡C-- and --CH₂--C≡C--CH₂ --, etc.).

Preferred are C₂₋₆ alkylene groups (e.g. ethylene, propylene,trimethylene, tetramethylene, pentamethylene, etc.), C₂₋₆ alkenylene(e.g. vinylene, propenylene, etc.), and C₂₋₆ alkynylene groups (e.g.ethynylene, propynylene, etc.)

The "aliphatic hydrocarbon group of at least 2 carbon atoms" may haveeither oxygen or sulfur within the carbon chain. Thus, for example,

--CH₂ --O--CH₂ --, --CH₂ --CH₂ --O--CH₂ --, --CH₂ --O--CH₂ O--CH₂ --,--CH₂ S--CH₂ --, --CH₂ --CH₂ --S--CH₂ --, and --CH₂ --S--CH₂ --S--CH₂--,

among others, can be mentioned.

The divalent aliphatic hydrocarbon group of the "divalent aliphatichydrocarbon group which may have either oxygen or sulfur within thecarbon chain" for P^(a) and Q^(a) includes a divalent group of one ormore carbon atoms which is available on elimination of hydrogen atomsfrom the same or different carbon atoms of saturated or unsaturatedaliphatic hydrocarbon and is preferably a group of 6 or fewer carbonatoms. More particularly, examples of the hydrocarbon group mentionedjust above include:

(i) alkylene groups (e.g. ##STR25## (ii) alkenylene groups (e.g.##STR26## (iii) alkinylene groups (e.g. --C≡C--, --CH₂ --C≡C--, and--CH₂ --C≡C--CH₂ --, etc.).

Preferred are C₂₋₆ alkylene (e.g. ethylene, propylene, trimethylene,tetramethylene, pentamethylene, etc.), C₂₋₆ alkenylene (e.g. vinylene,propenylene, etc.), and C₂₋₆ alkynylene (e.g. ethynylene, propynylene,etc.) in many instances.

The above "divalent aliphatic hydrocarbon group" may contain eitheroxygen or sulfur within the carbon chain. Thus, for example,

--CH₂ --O--CH₂ --, --CH₂ --CH₂ --O--CH₂ --, --CH₂ --O--CH₂ --O--CH₂,--CH₂ --S--CH₂ --, --CH₂ --CH₂ --S--CH₂ --, and --CH₂ --S--CH₂ --S--CH₂--

can be mentioned.

The "acyl group" for R^(1a) and R^(3a) includes, for example, --CO--R,--CONH--R, --SO--R, and --SO₂ --R wherein R represents an optionallysubstituted hydrocarbon group or an optionally substituted heterocyclicgroup. Particularly preferred is --CO--R in many instances.

The nitrogen-containing heterocyclic group of the "optionallysubstituted nitrogen-containing heterocyclic group" for R¹ and R², R³and R⁴, R^(1a) and R², or R^(3a) and R⁴ means a fused or non-fusednitrogen-containing heterocyclic group that may contain 1 to 3 heteroatoms of one or two kinds selected from among nitrogen, oxygen andsulfur.

The substituent which may be present on the "nitrogen-containingheterocyclic group" includes the substituents which may be present onAr¹ and Ar², among other groups. The "optionally substitutednitrogen-containing heterocyclic group" includes, for example, thefollowing. ##STR27## wherein ring A represents a 4- to 8-membered ringwhich may be substituted by 1 or 2 hydroxyl or oxo groups; Vrepresents >O, >C═O, ##STR28## or >N--W; W represents hydrogen, anoptionally substituted hydrocarbon group or an optionally substitutedheterocyclic group; and W^(a) represents hydrogen or hydroxyl; ##STR29##wherein ring B represents a 4- to 12-membered ring which may besubstituted by 1 or 2 oxo groups; ring D represents an optionallysubstituted 4- to 12-membered aromatic ring; preferably ##STR30##wherein ring B represents a 4- to 12-membered ring which may besubstituted by 1 or 2 oxo groups; D^(a) represents halogen (e.g.fluorine, chlorine, bromine, iodine), C₁₋₆ alkyl (e.g. methyl, ethyl,propyl, isopropyl, etc.), C₁₋₆ alkoxy (e.g. methoxy, ethoxy, propoxy,isopropoxy, etc.), C₁₋₃ alkylenedioxy (e.g. methylenedioxy,ethylenedioxy, etc.), nitro, amino or C₁₋₆ alkyl-carbonyl (e.g. acetyl,propionyl, etc.); ##STR31## wherein ring E represents an optionallysubstituted 5- to 10-membered aromatic ring; X represents --CH₂ --,--CO-- or --CH(OH)--; Y represents --CH₂ --, --O-- or --NW^(b) -- inwhich W^(b) represents hydrogen or an optionally substituted C₁₋₆ alkylgroup; k+m represents an integer of 1 to 4; and n represents an integerof 1 to 3;

(iv) optionally substituted nitrogen-containing heteroaromatic groups.Among others, (i), (ii) and (iii) are preferred. More preferred are (i)and (iii). Particularly (iii) is preferred.

The "4- to 8-membered ring which may be substituted by 1 or 2 hydroxylor oxo groups" for A includes, for example, the following. ##STR32##among others.

Preferred in many instances are ##STR33## wherein V is as defined aboveand G represents halogen such as fluorine, chlorine, etc.; C₁₋₆ alkylsuch as methyl, ethyl, propyl, isopropyl, etc.; or C₁₋₆ alkoxy such asmethoxy, ethoxy, propoxy, isopropoxy, etc.

The "optionally substituted hydrocarbon group" for W includes the groupsmentioned hereinbefore for the "optionally substituted hydrocarbongroup" for R, R¹ and R³. Particularly preferred are C₆₋₁₄ aryl (e.g.phenyl) and C₇₋₁₆ aralkyl (e.g. benzyl) groups. The substituent whichmay be present on this hydrocarbon group includes, for example, thesubstituents mentioned for the "hydrocarbon group" for R, R¹ and R³.

The "optionally substituted heterocyclic group" for W includes, forexample, 5- to 10-membered (monocyclic or bicyclic) heterocyclic groupscontaining 1 to 3 hetero atoms of 1 or 2 kinds selected from amongnitrogen, oxygen and sulfur in addition to carbon as ring members.Specifically, 1-, 2- or 3-pyrrolidinyl, 2- or 4-imidazolidinyl, 2-, 3-or 4-pyrazolidinyl, 1-, 2-, 3- or 4-piperidyl, 1- or 2-piperazinyl,morpholinyl, 2-thienyl, 3-thienyl, 2-pyridyl, 4-pyridyl, 2-furyl,3-furyl, 4-quinolyl, 8-quinolyl, 4-isoquinolyl, pyrazinyl,2-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl, 3-isothiazolyl,3-isoxazolyl, 1-indolyl, 2-isoindolyl, etc. can be mentioned. Preferred,among them, are aromatic groups. Particularly, 5- or 6-memberedheteroaromatic groups containing 1 to 3 hetero atoms selected from amongnitrogen, oxygen and sulfur in addition to carbon (e.g. 2-thienyl,3-thienyl, 2-pyridyl, 4-pyridyl, etc.) are preferred in many instances.

The substituent which may be present on the heterocyclic group of the"optionally substituted heterocyclic group" typically includes the samesubstituents as mentioned for the "optionally substituted aromaticgroup" for Ar¹ and Ar².

The 4- to 12-membered ring which may be substituted by 1 or 2 oxo groupsfor B includes, for example, the following: ##STR34##

The aromatic ring of the "optionally substituted 4- to 12-memberedaromatic ring" for D and E includes, for example, benzene ring,naphthalene ring, and 4- to 12-membered, preferably, 5- to 10-memberedheteroaromatic rings (e.g. rings containing 1 to 3 hetero atoms selectedfrom among N, O and S in addition to C as ring members, such aspyridine, pyrazine, pyrimidine, pyridazine, pyrrole, imidazole,pyrazole, thiophene, furan, thiazole, isothiazole, oxazole, isoxazole,quinoline, isoquinoline, indole, isoindole and other rings).Specifically, the following rings can be mentioned. ##STR35##

Ring D is preferably a benzene ring or a pyridine ring and morepreferably is a benzene ring. Ring E is preferably a benzene ring.

The substituent which may be present on the "optionally substitutedaromatic ring" includes the same substituents as mentioned hereinbeforefor the "optionally substituted aromatic group" for Ar¹ and Ar².

The "optionally substituted alkyl groups" for W^(b) includes, forexample, C₁₋₆ alkyl groups which may be substituted by 1 to 5substituents selected from the group consisting of halogen, C₁₋₃alkylenedioxy, nitro, cyano, optionally halogenated C₃₋₆ cycloalkyl,optionally halogenated C₁₋₆ alkoxy, optionally halogenated C₁₋₆alkylthio, hydroxyl, amino, mono-C₁₋₆ alkylamino, di-C₁₋₆ alkylamino,C₁₋₆ alkyl-carbonylamino, C₁₋₆ alkyl-carbonyl, carboxyl, C₁₋₆alkoxy-carbonyl, carbamoyl, mono-C₁₋₆ alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, sulfo, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₀aryl, C₆₋₁₀ aryloxy and 5- or 6-membered heterocyclic group.

The nitrogen-containing heteroaromatic group of the "optionallysubstituted nitrogen-containing heteroaromatic group" includes, forexample, 5- to 10-membered (monocyclic or bicyclic) heteroaromaticgroups containing one nitrogen atom other than carbon atom andoptionally having preferably 1 to 3 hetero atoms of 1 or 2 kindsselected from among N, O and S as ring members. Specifically, ##STR36##can be mentioned as examples. Where a counter ion is required, typicallya halide ion (e.g. chloride ion, bromide ion or iodide ion) is employed.

The substituent which may be present on the "optionally substitutednitrogen-containing heteroaromatic group" can be the same substituentsas those mentioned for the "optionally substituted aromatic group" forAr¹ and Ar².

Referring to the formulae shown hereinbefore, Ar¹ and Ar² independentlyrepresent an optionally substituted aromatic group. The aromatic groupsfor Ar¹ and Ar² may each be a C₆₋₁₀ aryl group (e.g. phenyl), forinstance.

The preferred "optionally substituted aromatic group" for Ar¹ and Ar²includes, for example, (i) C₆₋₁₄ aryl groups and (ii) 5- to 10-membered(monocyclic or bicyclic) heteroaromatic groups containing 1 to 3 heteroatoms selected from among nitrogen, oxygen and sulfur in addition tocarbon as ring members, which groups may optionally have 1-3substituents selected from the group consisting of halogen, C₁₋₃alkylenedioxy, nitro, cyano, optionally halogenated C₁₋₆ alkyl,optionally halogenated C₃₋₆ cycloalkyl, optionally halogenated C₁₋₆alkoxy, optionally halogenated C₁₋₆ alkylthio, hydroxyl, amino,mono-C₁₋₆ alkylamino, di-C₁₋₆ alkylamino, C₁₋₆ alkyl-carbonylamino,amino, C₁₋₆ alkyl-carbonyl, carboxyl, C₁₋₆ alkoxy-carbonyl, carbamoyl,mono-C₁₋₆ alkylcarbamoyl, di-C₁₋₆ alkylcarbamoyl, sulfo, C₁₋₆alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₀ aryl and C₆₋₁₀ aryloxy.

In the same formula, P and Q independently represent a divalentaliphatic hydrocarbon group of at least 2 carbon atoms which may haveeither oxygen or sulfur within the carbon chain.

Preferred examples of P and Q are C₂₋₆ alkylene and C₂₋₆ alkenylenegroups which may have either oxygen or sulfur within the carbon chain.Among them, C₂₋₆ alkylene and C₂₋₆ alkenylene groups are preferred, andC₃₋₅ alkylene groups (e.g. trimethylene, tetramethylene, etc.) are themore preferred in many instances.

In the formula (I') shown hereinbefore, P^(a) and Q^(a) independentlyrepresent a divalent aliphatic hydrocarbon group which may have eitheroxygen or sulfur within the carbon chain.

Preferred examples of P^(a) and Q^(a) are C₂₋₆ alkylene and C₂₋₆alkenylene groups which may have either oxygen or sulfur within thecarbon chain. Particularly preferred are C₂₋₆ alkylene and C₂₋₆alkenylene groups. Among them, C₃₋₅ alkylene groups (e.g. trimethylene,tetramethylene, etc.) are more preferred.

In the formula shown hereinbefore, R¹ and R³ independently represent i)an acyl group of --CO--R-- or --CONH--R wherein R represents anoptionally substituted hydrocarbon group or an optionally substitutedheterocyclic group or ii) an optionally substituted hydrocarbon group.

R¹ preferably represents an optionally substituted hydrocarbon group.

R³ preferably represents an acyl group of --CO--R or --CONH--R.

The "optionally substituted hydrocarbon group" for R, R¹ and R³ includes(i) C₁₋₆ alkyl, (ii) C₂₋₆ alkenyl, (iii) C₂₋₆ alkinyl, (iv) C₃₋₆cycloalkyl which may be fused with a phenyl ring, (v) C₆₋₁₄ aryl, and(vi) C₇₋₁₆ aralkyl, each optionally substituted by 1-3 substituentsselected from the group consisting of halogen, C₁₋₃ alkylenedioxy,nitro, cyano, optionally halogenated C₁₋₆ alkyl, optionally halogenatedC₃₋₆ cycloalkyl, optionally halogenated C₁₋₆ alkoxy, optionallyhalogenated C₁₋₆ alkylthio, hydroxyl, amino, mono-C₁₋₆ alkylamino,di-C₁₋₆ alkylamino, C₁₋₆ alkyl-carbonylamino, C₁₋₆ alkyl-carbonyl,carboxyl, C₁₋₆ alkoxy-carbonyl, carbamoyl, mono-C₁₋₆ alkylcarbamoyl,di-C₁₋₆ alkylcarbamoyl, sulfo, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl,C₆₋₁₀ aryl, C₆₋₁₀ aryloxy and 5- or 6-membered heterocyclic groups.

R¹ is preferably a C₇₋₁₆ aralkyl, C₃₋₆ cycloalkyl or benzo-C₃₋₆cycloalkyl group which may be substituted by 1 to 5 substituentsselected from the group consisting of halogen, optionally halogenatedC₁₋₆ alkyl, optionally halogenated C₁₋₆ alkoxy and C₁₋₆ alkoxy-carbonyl.

The preferred "optionally substituted heterocyclic group" for Rincludes, for example, 5- to 10-membered heterocyclic group which mayhave 1-3 substituents selected from the group consisting of halogen,C₁₋₃ alkylenedioxy, nitro, cyano, optionally halogenated C₁₋₆ alkyl,optionally halogenated C₃₋₆ cycloalkyl, optionally halogenated C₁₋₆alkoxy, optionally halogenated C₁₋₆ alkylthio, hydroxyl, amino,mono-C₁₋₆ alkylamino, di-C₁₋₆ alkylamino, C₁₋₆ alkyl-carbonylamino, C₁₋₆alkyl-carbonyl, carboxyl, C₁₋₆ alkoxy-carbonyl, carbamoyl, mono-C₁₋₆alkylcarbamoyl, di-C₁₋₆ alkyl-carbamoyl, sulfo, C₁₋₆ alkylsulfonyl, C₁₋₆alkylsulfinyl, C₆₋₁₀ aryl and C₆₋₁₀ aryloxy.

A preferred example of R³ is --CO--R. R³ is preferably an acyl group of--CO--R^(b) wherein R^(b) is a C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₆ cycloalkyl, C₆₋₁₄ aryl or C₇₋₁₆ aralkyl group which may besubstituted by 1 to 5 substituents selected from the group consisting ofhalogen, C₁₋₃ alkylenedioxy, nitro, cyano, optionally halogenated C₃₋₆cycloalkyl, optionally halogenated C₁₋₆ alkoxy, optionally halogenatedC₁₋₆ alkylthio, hydroxyl, amino, mono-C₁₋₆ alkylamino, di-C₁₋₆alkylamino, C₁₋₆ alkyl-carbonylamino, C₁₋₆ alkyl-carbonyl, carboxyl,C₁₋₆ alkoxy-carbonyl, carbamoyl, mono-C₁₋₆ alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, sulfo, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl and 5- or6-membered heterocyclic group. More preferred for R^(b) is a C₇₋₁₆aralkyl group which may have 1-3 substituents selected from amonghalogen, C₁₋₃ alkylenedioxy, nitro, cyano, optionally halogenated C₁₋₆alkyl, optionally halogenated C₃₋₆ cycloalkyl, optionally halogenatedC₁₋₆ alkoxy, optionally halogenated C₁₋₆ alkylthio, hydroxyl, amino,mono-C₁₋₆ alkylamino, di-C₁₋₆ alkylamino, C₁₋₆ alkyl-carbonylamino, C₁₋₆alkyl-carbonyl, carboxyl, C₁₋₆ alkoxy-carbonyl, carbamoyl, mono-C₁₋₆alkylcarbamoyl, di-C₁₋₆ alkylcarbamoyl, sulfo, C₁₋₆ alkylsulfonyl, C₁₋₆alkylsulfinyl, C₆₋₁₀ aryl and C₆₋₁₀ aryloxy. Particularly preferred isC₇₋₁₆ aralkyl group which may have 1-3 substituents selected from amonghalogen and C₁₋₆ alkoxy.

In the formula shown hereinbefore, R^(1a) and R^(3a) independentlyrepresent an acyl group or an optionally substituted hydrocarbon group.R^(1a) is preferably an optionally substituted hydrocarbon group. R^(3a)is preferably an acyl group.

In the formula, R² and R⁴ independently represent hydrogen or anoptionally substituted alkyl group.

The "optionally substituted alkyl" for R² and R⁴ includes, for example,C₁₋₆ alkyl having 1 to 3 substituents selected from among halogen,nitro, cyano, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, hydroxyl,amino, mono-C₁₋₆ alkylamino, di-C₁₋₆ alkylamino, C₁₋₆alkyl-carbonylamino, C₁₋₆ alkyl-carbonyl, carboxyl, C₁₋₆alkoxy-carbonyl, carbamoyl, mono-C₁₋₆ alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, sulfo, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl and C₆₋₁₀aryl.

Preferably R² is, for example, (i) hydrogen or (ii) C₁₋₆ alkyl which maybe substituted by phenyl (e.g. benzyl).

Preferably R⁴ is hydrogen.

In the formula shown hereinbefore, j represents 0 or 1. Preferably, j is0.

R¹ and R², R³ and R⁴, R^(1a) and R², or R^(3a) and R⁴, taken togetherwith the adjacent nitrogen atom, may form a nitrogen-containingheterocyclic group. This group ##STR37## may for example be: ##STR38##wherein Ring E^(a) represents an optionally substituted benzene ring,preferably a benzene ring optionally having 1-4 substituents selectedfrom among halogen, C₁₋₃ alkylenedioxy, nitro, cyano, optionallyhalogenated C₁₋₆ alkyl, optionally halogenated C₃₋₆ cycloalkyl,optionally halogenated C₁₋₆ alkoxy, optionally halogenated C₁₋₆alkylthio, hydroxyl, amino, mono-C₁₋₆ alkylamino, di-C₁₋₆ alkylamino,C₁₋₆ alkyl-carbonylamino, C₁₋₆ alkyl-carbonyl, carboxyl, C₁₋₆alkoxy-carbonyl, carbamoyl, mono-C₁₋₆ alkylcarbamoyl, di-C₁₋₆alkyl-carbamoyl, sulfo, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₀aryl and C₆₋₁₀ aryloxy, or ##STR39## wherein V^(a) represents ##STR40##or >N--W, in which W is a) hydrogen, b) a C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₄ aryl or C₇₋₁₆ aralkyl group which may besubstituted by 1 to 5 substituents selected from the group consisting ofhalogen, C₁₋₃ alkylenedioxy, nitro, cyano, optionally halogenated C₁₋₆alkyl, optionally halogenated C₃₋₆ cycloalkyl, optionally halogenatedC₁₋₆ alkoxy, optionally halogenated C₁₋₆ alkylthio, hydroxyl, amino,mono-C₁₋₆ alkylamino, di-C₁₋₆ alkylamino, C₁₋₆ alkyl-carbonylamino, C₁₋₆alkyl-carbonyl, carboxyl, C₁₋₆ alkoxy-carbonyl, carbamoyl, mono-C₁₋₆alkylcarbamoyl, di-C₁₋₆ alkylcarbamoyl, sulfo, C₁₋₆ alkylsulfonyl, C₁₋₆alkylsulfinyl and 5- or 6-membered heterocyclic group, or c) a 5- to10-membered heterocyclic group, containing, besides carbon atom, 1 to 4hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom,which may be substituted by 1 to 5 substituents selected from the groupconsisting of halogen, C₁₋₃ alkylenedioxy, nitro, cyano, optionallyhalogenated C₁₋₆ alkyl, optionally halogenated C₃₋₆ cycloalkyl,optionally halogenated C₁₋₆ alkoxy, optionally halogenated C₁₋₆alkylthio, hydroxyl, amino, mono-C₁₋₆ alkylamino, di-C₁₋₆ alkylamino,C₁₋₆ alkyl-carbonylamino, C₁₋₆ alkyl-carbonyl, carboxyl, C₁₋₆alkoxy-carbonyl, carbamoyl, mono-C₁₋₆ alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, sulfo, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₀aryl and C₆₋₁₀ aryloxy, and W^(a) is hydrogen or hydroxyl. W preferablyis phenyl group optionally having 1-3 substituents selected from amonghalogen and optionally halogenated C₁₋₆ alkoxy.

The following is a partial listing of some preferred compounds offormula (I).

(1) A compound of the formula: ##STR41## wherein Ar³ and Ar⁴independently represent an optionally substituted phenyl; Alk₁ and Alk₂independently represent a C₂₋₆ alkylene group; Ar⁵ represents anoptionally substituted aralkyl group; ring E^(a) represents anoptionally substituted benzene ring or a salt thereof.

Preferably, Ar³ and Ar⁴ are independently phenyl optionally having 1-3substituents selected from among halogen, C₁₋₃ alkylenedioxy, nitro,cyano, optionally halogenated C₁₋₆ alkyl, optionally halogenated C₃₋₆cycloalkyl, optionally halogenated C₁₋₆ alkoxy, optionally halogenatedC₁₋₆ alkylthio, hydroxyl, amino, mono-C₁₋₆ alkylamino, di-C₁₋₆alkylamino, C₁₋₆ alkyl-carbonylamino, C₁₋₆ alkyl-carbonyl, carboxyl,C₁₋₆ alkoxy-carbonyl, carbamoyl, mono-C₁₋₆ alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, sulfo, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₀aryl and C₆₋₁₀ aryloxy. More preferably they are optionally halogenatedphenyl.

Ar⁵ is preferably a C₇₋₁₆ aralkyl group (e.g. benzyl) optionally having1-3 substituents selected from among halogen, C₁₋₃ alkylenedioxy, nitro,cyano, optionally halogenated C₁₋₆ alkyl, optionally halogenated C₃₋₆cycloalkyl, optionally halogenated C₁₋₆ alkoxy, optionally halogenatedC₁₋₆ alkylthio, hydroxyl, amino, mono-C₁₋₆ alkylamino, di-C₁₋₆alkylamino, C₁₋₆ alkyl-carbonylamino, C₁₋₆ alkyl-carbonyl, carboxyl,C₁₋₆ alkoxy-carbonyl, carbamoyl, mono-C₁₋₆ alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, sulfo, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₀aryl and C₆₋₁₀ aryloxy. More preferably Ar^(5') is a C₇₋₁₆ aralkyl groupoptionally having 1-3 halogen or optionally halogenated C₁₋₃ alkoxysubstituents.

Ring E^(a) is preferably a benzene ring optionally having 1-3substituents selected from among halogen, C₁₋₃ alkylenedioxy, nitro,cyano, optionally halogenated C₁₋₆ alkyl, optionally halogenated C₃₋₆cycloalkyl, optionally halogenated C₁₋₆ alkoxy, optionally halogenatedC₁₋₆ alkylthio, hydroxyl, amino, mono-C₁₋₆ alkylamino, di-C₁₋₆alkylamino, C₁₋₆ alkyl-carbonylamino, C₁₋₆ alkyl-carbonyl, carboxyl,C₁₋₆ alkoxy-carbonyl, carbamoyl, mono-C₁₋₆ alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, sulfo, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₀aryl and C₆₋₁₀ aryloxy. Preferably ring E^(a) is a benzene ring whichmay be substituted by 1-3 substituents selected from among optionallyhalogenated C₁₋₃ alkoxy, C₁₋₃ alkyl-carbonyl and amino.

(2) A compound of the formula ##STR42## wherein V^(a) represents##STR43## or >N--W^(a), in which W is a) hydrogen, b) a C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₄ aryl or C₇₋₁₆ aralkylgroup which may be substituted by 1 to 5 substituents selected from thegroup consisting of halogen, C₁₋₃ alkylenedioxy, nitro, cyano,optionally halogenated C₁₋₆ alkyl, optionally halogenated C₃₋₆cycloalkyl, optionally halogenated C₁₋₆ alkoxy, optionally halogenatedC₁₋₆ alkylthio, hydroxyl, amino, mono-C₁₋₆ alkylamino, di-C₁₋₆alkylamino, C₁₋₆ alkyl-carbonylamino, C₁₋₆ alkyl-carbonyl, carboxyl,C₁₋₆ alkoxy-carbonyl, carbamoyl, mono-C₁₋₆ alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, sulfo, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl and 5- or6-membered heterocyclic group, or c) a 5- to 10-membered heterocyclicgroup, containing, besides carbon atom, 1 to 4 hetero atoms selectedfrom nitrogen atom, oxygen atom and sulfur atom, which may besubstituted by 1 to 5 substituents selected from the group consisting ofhalogen, C₁₋₃ alkylenedioxy, nitro, cyano, optionally halogenated C₁₋₆alkyl, optionally halogenated C₃₋₆ cycloalkyl, optionally halogenatedC₁₋₆ alkoxy, optionally halogenated C₁₋₆ alkylthio, hydroxyl, amino,mono-C₁₋₆ alkylamino, di-C₁₋₆ alkylamino, C₁₋₆ alkyl-carbonylamino, C₁₋₆alkyl-carbonyl, carboxyl, C₁₋₆ alkoxy-carbonyl, carbamoyl, mono-C₁₋₆alkylcarbamoyl, di-C₁₋₆ alkylcarbamoyl, sulfo, C₁₋₆ alkylsulfonyl, C₁₋₆alkylsulfinyl, C₆₋₁₀ aryl and C₆₋₁₀ aryloxy, and W^(a) is hydrogen orhydroxyl; the other symbols have the meanings defined hereinbefore or asalt thereof.

(3) A compound of the formula ##STR44## wherein ring B represents a 4-to 12-membered ring which may be substituted by 1 or 2 oxo groups; D^(a)represents halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₃ alkylenedioxy, nitro,cyano or C₁₋₆ alkyl-carbonyl; the other symbols have the meaningsdefined hereinbefore, or a salt thereof.

Referring to the above-mentioned compounds (1) to (3), Ar³ and Ar⁴ eachis preferably phenyl optionally having 1-3 substituents selected fromamong halogen and optionally halogenated C₁₋₆ alkoxy.

Referring, again, to the compounds (1) to (3), each of Alk₁ and Alk₂ ispreferably a C₃₋₅ alkylene group (e.g. trimethylene, tetramethylene,etc.).

Referring, further, to the compounds (1) to (3), Ar⁵ is preferably aC₇₋₁₆ aralkyl group which may be substituted by 1-3 substituentsselected from among halogen and optionally halogenated C₁₋₆ alkoxy.

Referring to the compound (1), ring E^(a) is preferably a benzene ringwhich may optionally be substituted by C₁₋₆ alkoxy optionally having 1-3halogen atoms.

Referring to the compound (2), W^(a) is preferably phenyl which may besubstituted by halogen (preferably one halogen atom).

The following compounds can be mentioned as further preferred examples,although this is not an exhaustive listing, of course.

(1)7-Acetylamino-1-{N-benzyl-N-[2-(6,7-dimethoxy-1,2,3,4-tetrahydronaphthyl)]amino}-4,4-diphenylheptanedihydrochloride,

(2)1'-(7-Acetylamino-4,4-diphenylheptyl)-3,4-dihydro-8-methoxyspiro[naphthalene-2(1H),2'-piperidine]dihydrochloride,

(3)1'-(7-Acetylamino-4,4-diphenylheptyl)-3,4-dihydro-6-methoxyspiro[naphthalene-2(1H),2'-piperidine]dihydrochloride,

(4)1'-(7-Acetylamino-4,4-diphenylheptyl)-3,4-dihydro-6,7-dimethoxyspiro[naphthalene-2(1H),2'-piperidine]dihydrochloride,

(5)3,4-Dihydro-6-methoxy-1'-(6-acetylamino-4,4-diphenylhexyl)spiro[naphthalene-2(1H),2'-piperidine]dihydrochloride,

(6)3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-[(phenylacetyl)amino]heptyl}spiro[naphthalene-2(1H),2'-piperidine]hydrochloride,

(7)3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-[(4-fluorophenylacetyl)amino]heptyl}spiro[naphthalene-2(1H),2'-piperidine]hydrochloride,

(8)3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-[(4-chlorophenylacetyl)amino]heptyl}spiro[naphthalene-2(1H),2'-piperidine]hydrochloride,

(9)3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-[(4-nitrophenylacetyl)amino]heptyl}spiro[naphthalene-2(1H),2'-piperidine]hydrochloride,

(10)3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-[(4-methoxyphenylacetyl)amino]heptyl}spiro[naphthalene-2(1H),2'-piperidine]hydrochloride,

(11)3,4-Dihydro-6,7-dimethoxy-1'-{7-[(3,4-dimethoxyphenylacetyl)amino]-4,4-diphenylheptyl}spiro[naphthalene-2(1H),2'-piperidine]hydrochloride,

(12)3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-[(3,4-methylenedioxyphenylacetyl)amino]heptyl}spiro[naphthalene-2(1H),2'-piperidine] hydrochloride,

(13)3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-[(phenoxyacetyl)amino]heptyl}spiro[naphthalene-2(1H),2'-piperidine]hydrochloride,

(14)3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-[(3-thienylacetyl)amino]heptyl}spiro[naphthalene-2(1H),2'-piperidine]hydrochloride,

(15)3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-[(3-phenylpropionyl)amino]heptyl}spiro[naphthalene-2(1H),2'-piperidine]hydrochloride,

(16)3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-{[3-(4-methoxyphenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine] hydrochloride,

(17)3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-{[3-(4-chlorophenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine] hydrochloride,

(18)3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-{[3-(4-fluorophenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine] hydrochloride,

(19)3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-[(1-naphthylacetyl)amino]heptyl}spiro[naphthalene-2(1H),2'-piperidine]hydrochloride,

(20)3,4-Dihydro-6,7-dimethoxy-1'-{4,4-bis(4-fluorophenyl)-7-[(4-methoxyphenylacetyl)amino]heptyl}spiro[naphthalene-2(1H),2'-piperidine] hydrochloride,

(21)N-(7-(6,7-Dimethoxy-1,2,3,4-tetrahydronaphthalene-2-spiro-2'-piperidin-1'-yl)-4,4-diphenyl-5-heptenyl)-3-(4-methoxyphenyl)propionamidehydrochloride,

(22)(+)-3,4-Dihydro-6-methoxy-1'-{4,4-diphenyl-7-{[(4-methoxyphenyl)acetyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine],

(23)(-)-3,4-Dihydro-6-methoxy-1'-{4,4-diphenyl-7-{[(4-methoxyphenyl)acetyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine],

(24)(-)-3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-{[(4-methoxyphenyl)acetyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine]-1-one,

(25)(-)-3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-{[(4-fluorophenyl)acetyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine],

(26)(+)-3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-{[(4-fluorophenyl)acetyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine],

(27)(-)-3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-{[3-(4-fluorophenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine],

(28)(+)-3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-{[3-(4-fluorophenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine],

(29)(+)-3,4-Dihydro-6,7-dimethoxy-1'-{7-{[3-(4-chlorophenyl)propionyl]amino}-4,4-diphenylheptyl}spiro[naphthalene-2(1H),2'-piperidine],

(30)(-)-3,4-Dihydro-6,7-dimethoxy-1'-{7-{[3-(4-chlorophenyl)propionyl]amino}-4,4-diphenylheptyl}spiro[naphthalene-2(1H),2'-piperidine],

(31)(-)-3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-{[3-(4-methoxyphenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine],

(32)(+)-3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-{[3-(4-methoxyphenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine].

In case compound (I) forms a salt and the salt is to be used as a drug,it is preferably a pharmaceutically acceptable salt.

The pharmaceutically acceptable salt includes, for example, salts withinorganic acids, such as the hydrochloride, sulfate, phosphate,diphosphate, hydrobromide, nitrate, etc., and salts with organic acids,such as the acetate, malate, maleate, fumarate, tartrate, succinate,citrate, lactate, methanesulfonate, p-toluenesulfonate, palmitate,salicylate, stearate, and so on.

While many synthetic technologies are feasible for producing thecompounds described in this specification, a typical productiontechnology is illustrated in the following schema 1. ##STR45##

The protective group of the acyl type, represented by R⁵, may forexample be formyl, acetyl, trifluoroacetyl, benzyloxycarbonyl,t-butoxycarbonyl or the like. The leaving group for L includes, forexample, halogen such as chlorine, bromine or iodine.

The compound wherein R¹ is R^(1a), R³ is R^(3a), P is P^(a) and Q isQ^(a) can also be produced by the above processes.

Process 1

The condensation reaction is carried out using 1-1.5 equivalents of acondensing agent, e.g. dicyclohexylcarbodiimide (DCC) or1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) orthrough a reactive intermediate of the carboxyl function. The reactiveintermediate may for example be the acid anhydride, acid halide oractivated ester.

The acid anhydride includes mixed acid anhydrides obtainable by reactionwith lower-alkyl chlorocarbonate (e.g. ethyl chlorocarbonate, isopropylchlorocarbonate, butyl chlorocarbonate, etc.) or with phenylchlorocarbonate.

The acid halide may for example be the acid chloride or acid bromide.The acid chloride can be obtained by, for example, stirring the startingcompound with at least 1 equivalent, preferably 3-10 equivalents, ofoxalyl chloride, thionyl chloride or phosphorus pentachloride in theabsence of a solvent or in an inert solvent such as dichloromethane at0° C.-100° C., preferably 30° C.-60° C., for 0.5-3 hours.

The activated ester includes esters with 1-hydroxybenzotriazole (HOBT),pentafluorophenol and so on.

The condensation reaction is generally carried out by reacting thestarting material with the corresponding amine in an inert solvent (e.g.dichloromethane, acetonitrile, etc.) stirring at 0°-80° C. for 0.5-20hours. The reaction can be conducted more smoothly in the presence of abase. While the base that can be used includes both inorganic andorganic bases, the preferred bases are triethylamine,diisopropylethylamine, 4-dimethylaminopyridine, N-methylmorpholine,4-pyrrolidylpyridine, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), and DBN,among other bases.

The reduction reaction can be carried out by the known technology (asdescribed in, for example, R. C. Larock, Comprehensive OrganicTransformation, VCH Publishers Inc.), for example by using a metalhydride or the like. This reaction can be carried out in an inertsolvent (e.g. ethers such as diethyl ether, diisopropyl ether, etc.)using at least one equivalent (preferably 4-10 equivalents) of a metalhydride at -20° C.-100° C., preferably 40° C.-80° C., for 5 minutes to18 hours.

The preferred metal hydride includes lithium aluminum hydride, aluminumhydride, diborane and analogs thereof, among others.

Conversion to the objective compound of this invention can be achievedby utilizing per se known reactions (e.g. reduction, alkylation,acylation, sulfonylation, or reaction with an isocyanate) incombination.

The acylation and sulfonylation reactions can be carried out insubstantially the same manner as the condensation reaction describedabove.

The reaction with an isocyanate can be carried out by reacting 1-1.5equivalents of an isocyanate compound with the starting compound in aninert solvent at 0° C.-50° C. for 0.1-10 hours. The presence of a base(catalytic amount to 1 equivalent) such as triethylamine may assist insmooth progress of the reaction.

The alkylation reaction is conducted in an inert solvent at atemperature of 0° C.-100° C. for a time period of 5 minutes to 100hours. The inert solvent includes alcoholic solvents (e.g. methanol,ethanol, propanol, etc.), ethereal solvents (e.g. diethyl ether,diisopropyl ether, etc.), halogen-containing solvents (e.g.dichloroethane, chloroform, etc.), aromatic solvents (e.g. toluene,xylene, etc.), acetonitrile, N,N-dimethylformamide (DMF), acetone,methyl ethyl ketone, dimethyl sulfoxide (DMSO) and so on. These solventscan be used singly or in combination. Particularly preferred areacetonitrile, DMF and acetone. The reaction can be conducted withgreater efficiency in the presence of a base. For this purpose, bothinorganic and organic bases are effective. The inorganic base that canbe used includes the hydroxides, carbonates, hydrogen carbonates, andorganic acid salts of alkali metals or alkaline earth metals and ispreferably selected from among potassium carbonate, sodium carbonate,sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, andpotassium hydrogen carbonate. The organic base is preferably a tertiaryamine such as triethylamine.

The leaving group is preferably chloro, bromo, iodo,p-toluenesulfonyloxy, or methanesulfonyloxy. Depending upon conditions,monoalkylation and dialkylation can be selectively carried out.

Process 2

The substitution of the leaving group with an amine (HN--R¹ R²) can becarried out by the conventional technology used for alkylation ofamines, for instance. For example, compound (5) is treated with thecorresponding amine (HN--R¹ R², 1-3 equivalents) in an inert solvent(e.g. DMF, acetone, or an ethereal solvent, used either alone or incombination), where necessary in the presence of 1-5 equivalents of abase (an inorganic base such as potassium carbonate or sodium hydroxideor an organic base such as triethylamine) stirring at a temperature of0° C.-100° C., preferably 30° C.-60° C., for a time period of 30 minutesto 24 hours.

The reduction step of cyano group can be carried out by the per se knowntechnology (as described in, for example, R. C. Larock, ComprehensiveOrganic Transformation, VCH Publishers Inc.). Among specific reactionsare reduction by means of a metal hydride and catalytic hydrogenation.

The reaction with a metal hydride can be carried out in an inert solvent(e.g. an ethereal solvent such as diethyl ether, diisopropyl ether,etc.) at a temperature of -20° C.-100° C., preferably 40° C.-80° C., fora time period of 5 minutes to 18 hours.

The preferred metal hydride includes lithium aluminum hydride, aluminumhydride, diborane, and analogs thereof, among others.

The catalytic reduction can be carried out using a metal catalyst suchas Raney nickel, platinum oxide, palladium metal, palladium-on-carbon orthe like in an alcoholic or ethereal solvent at a temperature of 10°C.-100° C. and a pressure of 3-50 atmospheres for 1-18 hours. Wherecompound (6) contains a double bond, the bond may also be reduced bythis catalytic reduction.

Process 3

Compound (7) can be transformed to compound (4') by a substitutionreaction similar to the reaction of Process 2. If required, theprotective group R⁵ on the N atom can be eliminated by a conventionalprocedure and, then, R³ and R⁴ are introduced to give compound (4).

The procedure for the deprotection reaction is dependent on the kind ofprotective group but generally the deprotection can be easily carriedout by the conventional hydrolysis reaction or catalytic reductionreaction.

The compound (4) thus obtained can be subjected to per se knownreactions (e.g. hydrolysis, oxidation, reduction, alkylation, acylation,etc.) to introduce new substituent groups into R¹, R², R³ and R⁴.

The starting compounds necessary for the above production processes canbe synthesized by various procedures. Typically, the following methodscan be mentioned.

The amino compound (NH--R¹ R²) used in the above process 1 to 3 can beobtained by a per se known process.Spiro[naphthalene-2(1H),2'-piperidine],spiro[naphthalene-2(1H),2'-morpholine], andspiro[naphthalene-2(1H),2'piperazine] can be synthesized according tothe process described in the reference example.Spiro[indane-2(1H),2'-pyrrolidine] can be synthesized following theprocedure written in Journal of Medicinal Chemistry, 21, 585(1978). Cis1,2,3,4,4a,9,10,10a,-octahydrobenzo[f]quinoline was also obtainedaccording to Synthesis, 494 (1986).

Among the compounds of compound (I), the compound wherein j is 1 can beobtained by standard procedures. For example, oxidation of the compound(4') in the above process 3 followed by deprotection and introduction ofR³ and R⁴ can produce the compound (I) wherein j is 1. ##STR46##

Compound (8) is reacted with an acrylate (e.g. methyl acrylate, ethylacrylate, benzyl acrylate, etc.), acrylonitrile or

    L--(CH.sub.2).sub.n T(CH.sub.2).sub.m --J.sup.1

(wherein T represents oxygen, sulfur, vinyl, or a chemical bond; n+m isan integer of 2 to 6; L represents a leaving group; J¹ represents loweralkoxycarbonyl or cyano) in a solvent, such as an ethereal solvent (e.g.diethyl ether, diisopropyl ether, etc.), DMF, DMSO, acetonitrile, analcoholic solvent (e.g. methanol, ethanol, etc.) or an aromatichydrocarbon (e.g. toluene, xylene, etc.), or a mixture of such solvents,in the presence of a base at a temperature of -20° C.-120° C. for 5minutes-18 hours to provide compound (9).

The base that can be used includes strong bases such as sodium hydride,potassium hydride, potassium t-butoxide, lithium diisopropylamide, etc.,inorganic bases such as the hydroxides, carbonates andhydrogencarbonates of alkali metals or alkaline earth metals such assodium hydroxide, potassium hydroxide, potassium carbonate, etc., andorganic bases such as triethylamine, DBU and so on.

When an acrylic ester or acrylonitrile is employed, the reaction isconducted in an alcoholic solvent, such as ethanol, in the presence of acatalytic amount to 5 equivalents of DBU under stirring at 40° C.-100°C. for 1-3 hours.

When L--(CH₂)_(n) T(CH₂)_(m) --J¹ is ethyl bromoacetate, ethyliodopropionate, or ethyl 4-bromobutyrate, the reaction is conducted inan ethereal solvent, such as tetrahydrofuran (THF), in the presence of1-3 equivalents of a strong base, such as sodium hydride, potassiumhydride, etc., at a temperature of -20° C. to 20° C. for a time periodof 5 minutes to 20 hours.

The substituent J² of compound (8) can be chain-extended by knowntechnology. Taking the case in which J² is formyl, the carbon chain canbe extended by means of, for example, Wittig reaction or Grignardreaction. For illustration, an example of synthesis of compound (I)starting from compound (10) is now presented.

The reaction with the Wittig reagent (e.g. ethyltriphenylphosphoranylideneacetate, ethyl diethylphosphonoacetate, etc.)can be conducted in an inert solvent (e.g. alcoholic solvents such asmethanol, ethanol, propanol, etc.), ethereal solvents such as diethylether, diisopropyl ether, etc.) or a mixture of such solvents, ifnecessary in the presence of a base (e.g. potassium carbonate, sodiumhydroxide, etc.; 1-2 equivalents), with stirring at 0° C.-80° C. for 10minutes to 2 hours to give the unsaturated carboxylic acid derivative.The double bond in this compound (11) can be easily reduced by catalyticreduction.

The catalytic reduction reaction can be carried out using a catalyticamount of metal catalyst such as Raney nickel, platinum oxide, palladiummetal, palladium-on-carbon, etc. in an alcoholic or ethereal solvent at10° C.-100° C., preferably room temperature, preferably under a pressureof 1-5 atmospheres for 1-18 hours.

The hydrolysis reaction can be easily carried out under acidic or basicconditions.

The basic hydrolysis reaction can be typically conducted using at leastone equivalent of an inorganic base such as sodium hydroxide, potassiumhydroxide or lithium hydroxide in an alcoholic solvent such as ethanolor a mixture of such solvent with water at a temperature of 10° C.-100°C., preferably at ambient temperature, for 0.5-20 hours. ##STR47##

Compound (5), which is used in Process 2, can be prepared by subjectingcompound (1) or an ester thereof [e.g. compound (11)] to selectivereduction of the cyano group to give the alcohol (12) and, then,introducing a leaving group.

The reduction reaction can be carried out by known technology [asdescribed in R. C. Larock, Comprehensive Organic Transformation, VCHPublishers Inc., and other literature]. Taking the reduction using ametal hydride as an example, the reaction can be conducted in an inertsolvent (e.g. ethereal solvents such as diethyl ether, diisopropylether, etc.) at a temperature of -20° C. to 100° C., preferably 10° C.to 50° C., for 5 minutes to 18 hours.

The preferred metal hydride includes lithium aluminum hydride, aluminumhydride, diborane, lithium borohydride, sodium borohydride, and analogsthereof.

Introduction of a leaving group for the hydroxyl group can be carriedout by per se known technology [as described in R. C. Larock,Comprehensive Organic Transformation, VCH Publishers Inc., among otherliterature]. The preferred leaving group is tosyloxy or iodo. Taking thetransformation to tosyloxy as an example, the reaction can be conductedusing p-toluenesulfonyl chloride (at least 1 equivalent, preferably1-1.5 equivalents) in a halogenated hydrocarbon solvent (e.g.dichloromethane, dichloroethane, etc.) in the presence of a base (1-5equivalents) such as triethylamine at a temperature of 0° C.-30° C. Thetransformation to iodo can be carried out either by reacting thetosyloxy compound with sodium iodide in an inert solvent (e.g. acetone)at 10° C.-100° C., preferably 30° C.-50° C., for 10 minutes to 6 hoursor by reacting compound (12) with iodine (1-3 equivalents, preferably 1equivalent) in an inert solvent in the presence of triphenylphosphine(1-5 equivalents, preferably 1 equivalent) at 10°-50° C. for 1-6 hours.##STR48##

Compound (5'), which is compound (5) wherein P represents vinylene, canbe derived from compound (9) by utilizing Grignard reaction. ##STR49##

When the Grignard reaction is utilized, compound (9) is reacted with avinylmetal reagent such as vinylmagnesium bromide, vinyllithium or thelike in an ethereal solvent (e.g. THF, ethyl ether, etc.) at atemperature of -50° C. to 30° C., preferably -10° C. to 0° C., for0.5-10 hours to give compound (13). This compound (13) can then behalogenated by reacting it with 1-5 equivalents of a suitablehalogenating agent (e.g. thionyl chloride, phosphorus tribromide, etc.)in an inert solvent such as a halogenated hydrocarbon solvent (e.g.dichloroethane, chloroform, etc.) or an ethereal solvent (e.g. ethylether, THF, etc.) at a temperature of -20° C. to 30° C., preferably 0°C.-20° C., for 0.1-20 hours.

The starting compound (7) which is used in Process 3 can be typicallysynthesized from compound (1) or an ester thereof by way of reduction.The method of introducing an N-protective group is dependent on the kindof protective group but formyl, acetyl, benzyloxycarbonyl, etc.,mentioned as preferred examples previously, can be introduced in thesame manner as the acylation reaction described hereinbefore.Introduction of the leaving group L can be carried out by per se knowntechnology (as described in R. C. Larock, Comprehensive OrganicTransformation, VCH Publishers Inc., among other literature) or anytechnology analogous thereto. ##STR50##

The objective compound of the invention and relevant starting materialsas well as their salts can be separated and purified by known proceduressuch as solvent extraction, pH change, redistribution, salting-out,crystallization, recrystallization, chromatography, etc. Theintermediate compounds need not be isolated but the reaction mixturescontaining them can respectively be submitted to the next reactionsteps.

Moreover, in case the starting compounds for any of the variousreactions of the invention or for any of the reactions for synthesizingthe various starting compounds, contain amino, carboxyl and/or hydroxylgroups, these functional groups may be previously protected withprotective groups which are commonly used in peptide chemistry orrelated art. The desired compounds can then be obtained by removing suchprotective groups when needed.

The amino-protective group that can be used includes, for example, C₁₋₆alkyl-carbonyl (e.g. formyl, acetyl, ethylcarbonyl, etc.),phenylcarbonyl, C₁₋₆ alkyloxycarbonyl (e.g. methoxycarbonyl,ethoxycarbonyl, etc.), benzoyl, C₇₋₁₀ aralkyl-carbonyl (e.g.benzylcarbonyl, etc), trityl, phthaloyl, and N,N-dimethylaminomethylene.These groups may respectively have 1-3 substituents selected from among,for example, halogen (e.g fluorine, chlorine, bromine, iodine, etc.) andnitro.

The carboxyl-protecting group which can be used includes, for example,C₁₋₆ alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl,etc.), phenyl, trityl, and silyl. These groups may respectively have 1-3substituents selected from among, for example, halogen (e.g. fluorine,chlorine, bromine, iodine), C₁₋₆ alkyl-carbonyl (e.g. formyl, acetyl,ethylcarbonyl, butylcarbonyl, etc.), and nitro.

The hydroxyl-protective group which can be used includes, for example,C₁₋₆ alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl,etc.), phenyl, C₇₋₁₀ aralkyl (e.g. benzyl etc.), C₁₋₆ alkyl-carbonyl(e.g. formyl, acetyl, ethylcarbonyl, etc.), benzoyl, C₇₋₁₀aralkyl-carbonyl (e.g. benzylcarbonyl), pyranyl, furanyl, and silyl.These groups may respectively have 1-3 substituents selected from among,for example, halogen (e.g. fluorine, chlorine, bromine, iodine), C₁₋₆alkyl (e.g. methyl, ethyl, n-propyl, etc.), phenyl, C₇₋₁₀ aralkyl (e.g.benzyl), and nitro.

These protective groups can be removed by per se known procedures or anyprocedures analogous thereto. For example, a process using an acid or abase, reduction, or a process using ultraviolet radiation, hydrazine,phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammoniumfluoride, or palladium acetate can be utilized.

The compound (I) of this invention, as well as its pharmaceuticallyacceptable salt, inhibits secretion of gonadotropic hormone on thestrength of its GnRH receptor antagonizing activity to control the bloodsteroid hormone concentrations. It therefore, can be safely used for thesuppression of ovulation or prevention of implantation of ova or in theprevention and treatment of amenorrhea, prostatic cancer, prostatichypertrophy, endometriosis, breast cancer, acne, precocious puberty,premenstrual syndrome, polycystic ovary syndrome, hyperandrogenism andother diseases in man. It is also effective in improving the quality ofmeat for food use.

The GnRH receptor antagonist composition of this invention, when used injudicious combination with a GnRH receptor agonist in mammals,especially in female persons, provides for adjustment and maintenance ofendogenous gonadotropin at the proper level and is also useful forinduction of ovulation.

The compound (I) of this invention, inclusive of its salt, has only alow toxic potential and a low risk of side effect. The oral acutetoxicity (LD₅₀) of the compound of this invention in rats is not lessthan 100 mg/kg.

The compound (I) of this invention, inclusive of its salt, can be safelyadministered as it is or as a pharmaceutical composition containing apharmaceutically acceptable carrier in various dosage forms such astablets (inclusive of dragees and film-coated tablets), powders,granules, capsules (inclusive of soft capsules), solutions, injections,suppositories, controlled-release preparations, etc., by the oral routeor by any other route. The dosage is dependent on the subject, route ofadministration, type and severity of disease, etc. but for the treatmentof prostatic cancer, for instance, the recommended oral regimen for anadult patient (b.wt. 60 kg) is 0.1-500 mg/day, preferably 10-100 mg/day,to be administered once a day or in a few divided doses daily.

The pharmaceutically acceptable carrier includes a variety of organicand inorganic carriers or vehicles which are commonly used in thepharmaceutical field. Here, excipients, lubricants, binders,disintegrators, etc. are all subsumed in the concept of carrier forsolid preparations, while solvents, solubilizers, suspending agents,isotonizing agents, buffers, smoothing agents (local analgesics), etc.can be used in the formulation of liquid preparations. Where necessary,various additives such as preservatives, antioxidants, coloring agents,sweeteners, etc. can also be added. The preferred excipient includes butis not limited to lactose, sucrose, D-mannitol, starch, crystallinecellulose, and light silicic anhydride. The preferred lubricant includesbut is not limited to magnesium stearate, calcium stearate, talc, andcolloidal silica. The preferred binder includes but is not limited tocrystalline cellulose, sucrose, D-mannitol, dextrin,hydroxypropylcellulose, hydroxypropylmethylcellulose, andpolyvinylpyrrolidone. The preferred disintegrator includes but is notlimited to starch, carboxymethylcellulose, carboxymethylcellulosecalcium, croscarmellose sodium, and carboxymethylstarch sodium. Thepreferred solvent includes but is not limited to water for injection,alcohol, propylene glycol, macrogols, sesame oil, and corn oil. Thepreferred solubilizer includes but is not limited to polyethyleneglycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol,trisaminomethane, cholesterol, triethanolamine, sodium carbonate, andsodium citrate. The preferred suspending agent includes surfactants suchas stearyl triethanolamine, sodium lauryl sulfate, laurylaminopropionicacid, lecithin, glycerin monostearate, etc. and hydrophilicmacromolecular substances such as polyvinyl alcohol,polyvinylpyrrolidone, carboxymethylcellulose sodium, methylcellulose,hydroxymethylcellulose, hydroxyethylcellulose, andhydroxypropylcellulose. The preferred isotonizing agent includes sodiumchloride, glycerin and D-mannitol. The preferred buffer includes variousbuffer solutions such as phosphate, acetate, carbonate, and citratebuffers, to name but a few. The preferred soothing agent includes but isnot limited to benzyl alcohol. The preferred preservative includes butis not limited to p-hydroxybenzoic esters, chlorobutanol, benzylalcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid. Thepreferred antioxidant includes but is not limited to salts of sulfurousacid, and ascorbic acid.

EXAMPLES

The following reference, working and test examples are intended todescribe this invention in further detail and should by no means beconstrued as defining the scope of the invention. Thus, various changesand modifications can be made without departing from the scope of theinvention.

In the following reference and working examples, the term "roomtemperature" means any temperature within the range of 0° to 30° C. Theother symbols have the following meanings.

    ______________________________________                                        s:           singlet                                                          d:           doublet                                                          t:           triplet                                                          q:           quartet                                                          m:           multiplet                                                        br:          broad                                                            ABq:         AB quartet                                                       dd:          double doublet                                                   J:           coupling constant                                                Hz:          Herz                                                             CDCl.sub.3 : deuterochloroform                                                THF:         tetrahydrofuran                                                  DMF:         N,N-dimethylformamide                                            DMSO:        dimethyl sulfoxide                                               .sup.1 H-NMR:                                                                              proton nuclear magnetic resonance                                ______________________________________                                    

Reference Example 1-1 3,3-Diphenyl-3-formylpropionitrile

To a solution of diphenylacetoaldehyde (1 g) in tetrahydrofuran (10 ml)was added a suspension of 60% sodium hydride (0.25 g) in tetrahydrofuran(5 ml) carefully dropwise under ice-cooling and stirring. Aftercompletion of dropwise addition, the mixture was further stirred for 20minutes. Then, bromoacetonitrile (0.41 ml) was added and the mixture wasfurther stirred for 30 minutes. The reaction mixture was poured inice-water and the oil that had separated out was extracted into ethylacetate. The organic layer was taken, washed with water, dried overanhydrous sodium sulfate, and concentrated to dryness. The group waspurified by silica gel column chromatography to provide the titlecompound (0.85 g) as colorless oil.

Reference Example 1-2 4,4-Diphenyl-4-formylbutyronitrile

Diphenylacetaldehyde (25.6 g), acrylonitrile (12.5 ml), and1,8-diazabicyclo[5,4,0]undec-7-ene (DBU:2.5 g) were stirred in isopropylalcohol (250 ml) with warming at 70° C. for 6 hours. The reactionmixture was concentrated to dryness and the group was purified by silicagel column chromatography. The crude crystal crop obtained was washedwith isopropyl ether to provide the title compound (19.8 g) as colorlesscrystals.

The structural formulas and NMR spectra of the respective compounds areshown in Table 1.

Reference Example 2-1 Ethyl 5-cyano-4,4-diphenyl-2-pentenoate

3,3-Diphenyl-3-formylpropionitrile (0.85 g) and(carbethoxymethylene)triphenylphosphorane (1.46 g) were heated inchloroform (20 ml) on reflux for 7 hours. The reaction mixture was thenconcentrated to dryness and the group was purified by silica gel columnchromatography to provide the title compound (0.7 g) as colorless oil.

The compound of Reference Example 2-2 was synthesized in the same manneras Reference Example 2-1.

Reference Example 2-2 Ethyl 6-cyano-4,4-diphenyl-2-hexenoate

The structural formulas and NMR spectra of the above compounds are shownin Table 2.

Reference Example 3-1 (4-Chlorophenyl)phenylacetonitrile

To a mixture of mandelonitrile (5 g) and chlorobenzene (15.7 g) wasadded sulfuric acid (9.8 ml) dropwise while the temperature of themixture was maintained at 5°-10° C. After completion of dropwiseaddition, the mixture was stirred for another 1.5 hours. This reactionmixture was poured in ice-water and the syrup that had separated out wasextracted into ethyl acetate. The extract was washed with saturatedaqueous sodium hydrogen carbonate solution, dried over anhydrous sodiumsulfate, and concentrated to dryness. The group was purified by silicagel column chromatography to provide the title compound (3.6 g) as paleyellow syrup.

The compounds of Reference Examples 3-2 and 3 were synthesized in thesame manner as Reference Example 3-1.

Reference Example 3-2

(4-Methoxyphenyl)phenylacetonitrile

Reference Example 3-3

Bis(4-chlorophenyl)acetonitrile

The structural formulas and NMR spectra of the respective compounds areshown in Table 3.

Reference Example 4-1 Ethyl 4-cyano-4,4-diphenylbutyrate

To a solution of diphenylacetonitrile (28 g) in ethanol (100 ml) wereadded DBU (6 ml) and ethyl acrylate (30 ml), and the mixture was heatedand stirred at 80° C. for 16 hours. After cooling, 2N-hydrochloric acid(200 ml) was added and the mixture was extracted with isopropyl ether.The organic layer was washed with water, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The crude crystal cropwas recrystallized from hexaneisopropyl ether to provide the titlecompound (34 g).

The compounds of Reference Example 4-2 through 4-4 were synthesized inthe same manner as Reference Example 4-1.

Reference Example 4-2

Ethyl 4-(4-chlorophenyl)-4-cyano-4-phenylbutyrate

Reference Example 4-3

Ethyl 4-cyano-4-(4-methoxyphenyl)-4-phenylbutyrate

Reference Example 4-4

Ethyl 4,4-bis(4-chlorophenyl)-4-cyanobutyrate

Reference Example 4-5 Ethyl 5-cyano-5,5-diphenylpentanoate

To a stirring solution of diphenylacetonitrile (1-g) in tetrahydrofuran(10 ml) was added 60% sodium hydride (0.25 g) in small portions underice-cooling. After completion of dropwise addition, the mixture wasstirred for 20 minutes. Then, ethyl 4-bromobutyrate (0.94 ml) was addeddropwise under ice-cooling and the mixture was further stirred at roomtemperature for 15 minutes. This reaction mixture was poured intoice-water and the organic layer that had separated out was extractedwith ethyl acetate. The extract was washed with water, dried overanhydrous sodium sulfate, and concentrated to dryness. The group waspurified by silica gel column chromatography to provide the titlecompound (0.87 g) as colorless oil.

Reference Example 4-6 Ethyl 5-cyano-4,4-diphenylpentanoate

To a solution of ethyl 5-cyano-4,4-diphenyl-2-pentenoate (0.7 g) inethanol (20 ml) was added 10% palladium-on-carbon (0.24 g), and themixture was subjected to catalytic hydrogenation at atmospheric pressureand temperature. The catalyst in the reaction mixture was filtered offand the filtrate was concentrated to dryness. The group was purified bysilica gel column chromatography to provide the title compound (0.6 g)as colorless oil.

The compound of Reference Example 4-7 was synthesized in same manner asReference Example 4-6.

Reference Example 4-7 Ethyl 6-cyano-4,4-diphenylhexanoate

The structural formulas and NMR spectra of the respective compounds areshown in Table 4.

Reference Example 5-1 5-Amino-4,4-diphenylpentanol

To a stirred solution of ethyl 4-cyano-4,4-diphenylbutyrate (1.2 g) intetrahydrofuran (30 ml) was added lithium aluminum hydride (0.44 g) insmall portion under ice-cooling. After completion of dropwise addition,the mixture was heated and stirred at 60° C. for 3 hours. The reactionmixture was then cooled with ice again, and water (1 ml), 15% aqueoussodium hydroxide (3 ml) and water (1 ml) were added in succession. Theinsoluble matter that had separated out was filtered off and thefiltrate was extracted with ethyl acetate and saturated aqueous sodiumhydrogen carbonate. The organic layer was taken, washed with water,dried over anhydrous sodium sulfate, and concentrated to dryness. Thegroup was washed with isopropyl ether to provide the title compound(0.82 g) as colorless powder.

The compounds of Reference Examples 5-2 through 5-7 were synthesized inthe same manner as Reference Example 5-1.

Reference Example 5-2

5-Amino-4-(4-chlorophenyl)-4-phenylpentanol

Reference Example 5-3

5-Amino-4-(4-methoxyphenyl)-4-phenylpentanol

Reference Example 5-4

5-Amino-4,4-bis(4-chlorophenyl)pentanol

Reference Example 5-5

6-Amino-5,5-diphenylhexanol

Reference Example 5-6

6-Amino-4,4-diphenylhexanol

Reference Example 5-7

7-Amino-4,4-diphenylheptanol

The structural formulas and NMR spectra of the respective compounds areshown in Table 5.

Reference Example 6-1 5-Formylamino-4,4-diphenylpentanol

In formic acid (80 ml) was dissolved 5-amino-4,4-diphenylpentanol (10 g)followed by addition of acetic anhydride (13 ml) and the mixture wasstirred at room temperature for 4 hours. This reaction mixture wasconcentrated to dryness and the group was partitioned into chloroformand water. The water layer was made basic by aqueous ammonia andextracted with chloroform. The extract was dried over anhydrous sodiumsulfate and concentrated to dryness. The group was dissolved in ethanol(30 ml) and the solution was stirred in 1N-aqueous sodium hydroxide (20ml) at room temperature for 20 minutes. This reaction mixture wasdiluted with water and the crystals that separated out were harvested byfiltration. This crystal crop was washed serially with water and ethylacetate to provide the title compound (9 g) as colorless powder.

The compounds of Reference Example 6-2 through 6-7 were synthesized inthe same manner as Reference Example 7-1.

Reference Example 6-2

4-(4-Chlorophenyl)-5-formylamino-4-phenylpentanol

Reference Example 6-3

5-Formylamino-4-(4-methoxyphenyl)-4-phenylpentanol

Reference Example 6-4

4,4-Bis(4-chlorophenyl)-5-formylaminopentanol

Reference Example 6-5

6-Formylamino-5,5-diphenylhexanol

Reference Example 6-6

6-Formylamino-4,4-diphenylhexanol

Reference Example 6-7

7-Acetylamino-4,4-diphenylheptanol

The structural formulas, physical properties, and NMR spectra of theabove compounds are shown in Table 6.

Reference Example 7-1 5-Formylamino-1-iodo-4,4-diphenylpentane

To a solution of 5-formylamino-4,4-diphenylpentanol (38.3 g) inmethylene chloride (600 ml) were added p-toluenesulfonyl chloride (29.2g), triethylamine (15 g), and 4-(dimethylamino)pyridine (catalyticamount), and the mixture was stirred at room temperature for 4 hours.The reaction mixture was concentrated to dryness, and sodium iodide(46.6 g) and acetone (600 ml) were added to the group. The reactionmixture was heated and stirred at 50° C. for 2 hours, after which it wasconcentrated to dryness. The group was extracted with ethyl acetate andwater. The organic layer was taken, washed with an aqueous solution ofsodium thiosulfate, dried over anhydrous sodium sulfate, andconcentrated to dryness. The group was purified by silica gel columnchromatography to provide the title compound (46.5 g) as yellow syrup.The compounds of Reference Example 7-3, 7-4, 7-6, 7-7, and 7-9 wererespectively synthesized in the same manner as Reference Example 7-1.

Reference Example 7-3

4-(4-Chlorophenyl)-5-formylamino-1-iodo-4-phenylpentane

Reference Example 7-4

5-Formylamino-1-iodo-4-(4-methoxyphenyl)-4-phenylpentane

Reference Example 7-6

6-Formylamino-1-iodo-5,5-diphenylhexane

Reference Example 7-7

6-Formylamino-1-iodo-4,4-diphenylhexane

Reference Example 7-9

7-Acetylamino-1-iodo-4,4-diphenylheptane

Reference Example 7-2 1-Iodo-4,4-diphenyl-5-(tosylamino)pentane

5-Amino-4,4-diphenylpentanol (1 g), p-toluenesulfonyl chloride (1.65 g),triethylamine (1.2 ml), and 4-(dimethylamino)pyridine (catalytic amount)were stirred in methylene chloride (20 ml) at room temperatureovernight. This reaction mixture was concentrated to dryness and thegroup was stirred with sodium iodide (0.7 g) in acetone (25 ml) at 50°C. for 24 hours. The reaction mixture was concentrated to dryness andthe group was extracted using ethyl acetate and water. The organic layerwas dried over anhydrous sodium sulfate and concentrated to dryness toprovide the title compound (1 g) as light-yellow powder.

The compounds of Reference Example 7-8 and 7-5 were synthesized in thesame manner as Reference Example 7-2.

Reference Example 7-8

1-Iodo-4,4-diphenyl-6-(tosylamino)hexane

Reference Example 7-5

4,4-Bis(4-chlorophenyl)-5-(formylamino)pentyl tosylate

The structural formulas, physical properties, and NMR spectra of therespective compounds are shown in Table 7.

Reference Example 8

5-Cyano-4,4-diphenylpentanol

To a stirred solution of ethyl 5-cyano-4,4-diphenylpentanoate (2 g) intetrahydrofuran (25 ml) was added lithium aluminum hydride (0.37 g) insmall portions under ice-cooling. After completion of addition, themixture was further stirred for 30 minutes. While the reaction mixturewas stirred under ice-cooling, water (0.9 ml), 15% aqueous sodiumhydroxide (2.7 ml), and water (0.9 ml) were added in the ordermentioned. The insoluble matter that separated out was filtered off andthe filtrate was extracted with ethyl acetate and saturated aqueoussodium hydrogen carbonate. The organic layer was washed with saturatedaqueous sodium chloride, dried over anhydrous sodium sulfate, andconcentrated to dryness. The group was purified by silica gel columnchromatography to provide the title compound (1.3 g) as colorless syrup.

¹ H-NMR(CDCl₃, δ): 1.25-1.40(2H,m), 2.34-2.43(2H,m), 3.12(2H,s),3.61(2H,t), 7.15-7.37(10H,m)

Reference Example 9 3,3-Diphenyl-6-iodohexanenitrile

To a solution of triphenylphosphine (1.68 g) in methylene chloride (30ml) and imidazole (0.44 g) was added iodine (1.62 g). To this mixturewas added a solution of 5-cyano-4,4-diphenylpentanol (1.3 g) inmethylene chloride (5 ml) dropwise. After completion of dropwiseaddition, the mixture was stirred at room temperature overnight. Thereaction mixture was washed with a saturated aqueous solution of sodiumthiosulfate, dried over anhydrous sodium sulfate, and concentrated todryness. To the group was added isopropyl ether, and the insolublematter was filtered off. The filtrate was concentrated to dryness toprovide the title compound (1.5 g) as colorless syrup.

¹ H-NMR(CDCl₃, δ): 1.49-1.64(2H,m), 2.38-2.47(2H,m), 3.11(2H,s),3.12(2H,t), 7.13-7.39(10H,m)

Reference Example 10 6-Cyano-4,4-diphenylhexanoic Acid

To a solution of ethyl 6-cyano-4,4-diphenylhexanoate (25.5 g) in ethanol(400 ml) was added 1N-aqueous sodium hydroxide solution (120 ml) and themixture was heated and stirred at 60° C. for 1 hour. After completion ofthe reaction, the reaction mixture was concentrated under reducedpressure and the group was made acidic to with 1N-hydrochloric acid andextracted with ethyl acetate (200 ml×2). The extract was washed withsaturated aqueous sodium chloride solution, dried over anhydrous sodiumsulfate, and concentrated to dryness. The group (25 g) wasrecrystallized from chloroform-hexane to provide the title compound (22g) as white powder.

m.p. 119°-120° C. ¹ H-NMR(CDCl₃, δ): 1.95-2.10(4H,m), 2.37-2.50(4H,m),7.10-7.40(10H,m)

Reference Example 113,4-Dihydro-6,7-dimethoxy-1'-(6-cyano-4,4-diphenylhexanoyl)spiro[naphthalene-2(1H),2'-piperidine]

To a stirred solution of 6-cyano-4,4-diphenylhexanoic acid (1.6 g) inchloroform (20 ml) was added thionyl chloride (0.79 ml) dropwise underice-cooling. After completion of dropwise addition, the mixture wasfurther stirred at room temperature for 1 hour. This reaction mixturewas concentrated to dryness under reduced pressure and the group wasdissolved in methylene chloride (5 ml). This solution was added dropwiseto a solution of3,4-dihydro-6,7-dimethoxyspiro[naphthalene-2(1H),2'-piperidine]hydrochloride(1.96 g) and triethylamine (1.33 g) in methylene chloride (25 ml) underice-cooling and stirring. After completion of dropwise addition, themixture was further stirred at room temperature for 30 minutes. Thisreaction mixture was concentrated to dryness and the group was purifiedby silica gel column chromatography to provide the title compound (1.29g) as light-yellow syrup.

¹ H-NMR(CDCl₃, δ): 1.52-1.68(6H,m), 1.91-2.09(4H,m), 2.34-2.60(5H,m),2.62-2.98(4H,m), 3.08-3.16 (2H,m), 3.83(6H,s), 3.96(1H,d), 6.55,6.58(1H,each,s), 7.11-7.37(10H,m)

Reference Example 123,4-Dihydro-6-methoxy-1'-(5-cyano-4,4-diphenylpentyl)spiro[naphthalene-2(1H),2'-piperidine]hydrochloride

3,3-Diphenyl-6-iodohexanenitrile (1.5 g),3,4-dihydro-6-methoxyspiro[naphthalene-2(1H),2'-piperidine]hydrochloride(1.39 g), triethylamine (0.53 g), and potassium carbonate (0.72 g) werestirred in acetonitrile (25 ml) at 70° C. overnight. The insolublematter in the reaction mixture was filtered off and the filtrate wasconcentrated to dryness. The group was purified by silica gel columnchromatography to provide the hydrochloride salt of the title compound(0.7 g) as light-yellow powder.

¹ H-NMR(CDCl₃, δ): 1.09-1.25(2H,m), 1.38-1.70(7H,m), 1.78-1.95(1H,m),2.13-2.80(10H,m), 3.08(2H,s), 3.77(3H,s), 6.62-6.71(2H,m), 6.95(1H,d),7.12-7.37(10H,m)

Elemental analysis: C₃₃ H₃₈ N₂ O.HCl.H₂ O. Calcd. C 74.38; H 7.88; N5.38. Found C 74.34; H 7.75; N 5.25

                  TABLE 1                                                         ______________________________________                                         ##STR51##                                                                    Reference                                                                     Example X     Y     m   .sup.1 H-NMR (δ ppm, CDCl.sub.3)                ______________________________________                                        1-1     H     H     2   3.24(2H, s), 7.19-7.50(10H, m),                                               9.79(1H, s)                                           1-2     H     H     3   2.04-2.13(2H, m), 2.64-2.74(2H, m),                                           7.11-7.45(10H, m), 9.79(1H, s)                        ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                         ##STR52##                                                                    Reference                                                                     Example X      Y     m    .sup.1 H-NMR (δ ppm, CDCl.sub.3)              ______________________________________                                        2-1     H      H     2    1.29(3H, t), 3.28(2H, s), 4.21(2H, q),                                        5.71, 7.52(1H each, d),                                                       7.14-7.41(10H, m)                                   2-2     H      H     3    1.29(3H, t), 2.09-2.18(2H, m),                                                2.65-2.77(2H, m), 4.20(2H, q),                                                5.63, 7.47(1H each, d),                                                       7.09-7.19(4H, m), 7.22-7.40(6H,                     ______________________________________                                                                  m)                                              

                  TABLE 3                                                         ______________________________________                                         ##STR53##                                                                    Reference                                                                     Example X       Y      .sup.1 H-NMR (δ ppm, CDCl.sub.3)                 ______________________________________                                        3-1     4-Cl    H      5.11(1H, s), 7.23-7.42(9H, m)                          3-2     4-MeO   H      3.80(3H, s), 5.10(1H, s), 6.85-6.94(2H,                                       m), 7.20-7.40(7H, m)                                   3-3     4-Cl    4-Cl   5.10(1H, s), 7.20-7.40(8H, m)                          ______________________________________                                    

                                      TABLE 4                                     __________________________________________________________________________     ##STR54##                                                                    Reference                                                                     Example                                                                             X    Y  m  n .sup.1 H-NMR (δ ppm, CDCl.sub.3)                     __________________________________________________________________________    4-1   H    H  1  3 1.23(3H, t), 2.40-2.51(2H, m), 2.71-2.82(2H, m),                              4.11(2H, q), 7.26-7.43(10H, m)                             4-2   4-Cl H  1  3 1.23(3H, t), 2.38-2.48(2H, m), 2.78-2.88(2H, m),                              4.10(2H, q), 7.29-7.40(9H, m)                              4-3   4-MeO                                                                              H  1  3 1.60-1.85(2H, m), 2.23-2.50(2H, m), 3.69(2H, t),                              3.79(3H, s) 6.88-6.90(2H, m), 7.10-7.40(7H, m)             4-4   4-Cl 4-Cl                                                                             1  3 1.23(3H, t), 2.41(2H, m), 2.70(2H, m), 4.10(2H, q),                           7.20-7.40(8H, m)                                           4-5   H    H  1  4 1.24(3H, t), 1.69-1.86(2H, m), 2.38(2H, t),                                   2.38-2.48(2H, m), 4.12(2H, q), 7.23-7.43(10H, m)           4-6   H    H  2  3 1.21(3H, t), 2.09, 2.66(2H each, t), 3.09(2H, s),                             4.06(2H, q), 7.16-7.39(10H, m)                             4-7   H    H  3  3 1.22(3H, t), 1.95-2.06(4H, m), 2.36-2.48(4H, m),                              4.07(2H, q), 7.09-7.37(10H, m)                             __________________________________________________________________________

                                      TABLE 5                                     __________________________________________________________________________     ##STR55##                                                                    Reference        Melting                                                      Example                                                                             X   Y  m n Point(°C.)                                                                   .sup.1 H-NMR (δ ppm, CDCl.sub.3)                 __________________________________________________________________________    5-1   H   H  1 3 syrup                                                        5-2   4-Cl                                                                              H  1 3 syrup 1.17-1.33(2H, m), 1.55(2H, br s), 2.14-2.44(2H, m)                            3.31(2H, s), 3.56(2H,                                                         t), 7.07-7.38(9H, m)                                   5-3   4-MeO                                                                             H  1 3 syrup 1.20-1.35(2H, m), 2.15-2.25(2H, m), 3.31(2H, s),                              3.57(2H, t), 3.79(3H, s),                                                     6.78-6.85(2H, m), 7.05-7.35(7H, m)                     5-4   4-Cl                                                                              4-Cl                                                                             1 3 syrup 1.10-1.30(2H, m), 1.55(2H, br s), 2.14-2.24(2H,                               m), 3.29(2H, s), 3.55(2H,                                                     t), 7.00-7.30(8H, m)                                   5-5   H   H  1 4 syrup 1.01-1.18(2H, m), 1.42-1.65(4H, m), 2.09-2.20(2H,                             m), 3.33(2H, s), 3.56                                                         (2H, t), 7.12-7.35(10H, m)                             5-6   H   H  2 3 syrup 1.14-1.32(2H, m), 2.10-2.26(2H, m), 2.24-2.39(2H,                             m), 2.37-2.51(2H, m),                                                         3.15(3H, s), 3.51(2H, t), 7.07-7.30(10H, m)            5-7   H   H  3 3 syrup 1.10-1.31(4H, m), 2.05-2.22(4H, m), 2.66, 3.53(2H                             each, t), 3.01(3H, brs),                                                      7.06-7.30(10H, m)                                      __________________________________________________________________________

                                      TABLE 6                                     __________________________________________________________________________     ##STR56##                                                                    Reference              Melting                                                Example                                                                             X    Y  R   m  n Point(°C.)                                                                   .sup.1 H-NMR (δ ppm,                       __________________________________________________________________________                                 CDCl.sub.3)                                      6-1   H    H  CHO 1  3 151-152                                                                             1.32(2H, m), 2.16(2H, m), 3.55(2H, t),                                        4.05(2H, d), 5.10-5.30(1H, m),                                                7.10-7.40(10H, m), 8.08(1H, d)                   6-2   4-Cl H  CHO 1  3 159-161                                                                             1.00-1.23(2H, m), 2.03(2H, t), 3.30(2H, q),                                   3.88(2H, dd), 4.33(1H, t),                                                    7.10-7.37(9H, m), 7.48(1H, br t), 7.87(1H,                                    d)                                               6-3   4-MeO                                                                              H  CHO 1  3 syrup 1.20-1.40(2H, m), 2.08-2.20(2H, m), 3.54(2H,                                  br t), 3.79(3H, s), 4.01                                                      (2H, dt), 5.20-5.30(1H, br s), 6.80-6.88(2H,                                  m), 7.00-7.35(7H, m), 8.07                                                    (1H, d)                                          6-4   4-Cl 4-Cl                                                                             CHO 1  3 175-178                                                                             1.00-1.20(2H, m), 2.04(2H, t), 3.30(2H, q),                                   3.86(2H, d), 4.34(1H, t),                                                     7.10-7.40(8H, m), 7.55(1H, br t), 7.88(1H,                                    d)                                               6-5   H    H  CHO 1  4 syrup 1.04-1.22(2H, m), 1.40-1.56(2H, m),                                           1.90-2.18(2H, m), 3.54(2H, t), 4.06                                           (2H, d), 5.20(1H, br t), 7.10-7.37(10H, m),                                   8.08(1H, d)                                      6-6   H    H  CHO 2  3 syrup 1.20-1.38(2H, m), 2.20-2.40(4H, m), 3.06(2H,                                  q), 3.57(2H, t), 5.49                                                         (1H, br), 7.10-7.34(10H, m), 7.99(1H, d)         6-7   H    H  Ac  3  3 syrup 1.12-1.30(4H, m), 1.90(3H, s), 2.02-2.21(5H,                                  m), 3.15(2H, q), 3.55(2H,                                                     t), 5.49(1H, br t), 7.11-7.30(10H,               __________________________________________________________________________                                 m)                                           

                                      TABLE 7                                     __________________________________________________________________________     ##STR57##                                                                    Reference                Melting                                              Example                                                                             X   Y  R   L  m n  Point(°C.)                                                                   .sup.1 H-NMR (δ ppm,                     __________________________________________________________________________                                   CDCl.sub.3)                                    7-1   H   H  CHO I  1 3  syrup 1.49-1.65(2H, m), 2.12-2.25(2H, m),                                           3.10(2H, t), 4.04(2H, d), 5.07                                                (1H, br t), 7.11-7.40(10H, m), 8.11(1H,                                       d)                                             7-2   H   H  Ts  I  1 3  syrup 1.31-1.49(2H, m), 2.15-2.26(2H, m),                                           2.44(3H, s), 2.99(2H, t), 3.54                                                (2H, d), 3.87(1H, t), 7.05, 7.06, 7.64(2H                                     each, d), 7.20-7.35(8H, m)                     7-3   4-Cl                                                                              H  CHO I  1 3  syrup 1.46-1.63(2H, m), 2.10-2.22(2H, m),                                           3.10(2H, t), 4.01(2H, d), 5.08                                                (1H, br t), 7.06-7.39(9H, m), 8.10(1H, d)      7-4   4-MeO                                                                             H  CHO I  1 3  syrup 1.45-1.65(2H, m), 2.09-2.22(2H, m),                                           3.09(2H, t), 3.80(3H, s), 3.99                                                (2H, d), 5.00-5.15 (1H, br s),                                                6.80-6.90(2H, m), 7.00-7.38(7H, m),                                           8.10(1H, d)                                    7-5   4-Cl                                                                              4-Cl                                                                             CHO OTs                                                                              1 3  syrup 1.30-1.60(2H, m), 2.00-2.20(2H, m),                                           2.45(3H, s), 3.90-4.00(4H, m),                                                5.00-5.20(1H, br s), 7.00-7.40(10H, m),                                       7.72(2H, m), 8.08(1H, d)                       7-6   H   H  CHO I  1 4  syrup 1.07-1.28(2H, m), 1.65-1.85(2H, m),                                           2.00-2.13(2H, m), 3.07(2H, t),                                                4.04(2H, d), 5.02(1H, br s),                                                  7.10-7.39(10H, m), 8.10(1H, d)                 7-7   H   H  CHO I  2 3  syrup 1.43-1.61(2H, m), 2.19-2.40(4H, m),                                           3.08(2H, q), 3.11(2H, t), 5.19                                                (1H, br s), 7.12-7.36(10H, m), 7.99(1H,                                       d)                                             7-8   H   H  Ts  I  2 3  syrup 1.32-1.49(2H, m), 2.02-2.17(2H, m),                                           2.21-2.34(2H, m), 2.42(3H, s),                                                2.62-2.78(2H, m), 3.05(2H, t), 4.26(1H,                                       t), 7.06, 7.07, 7.61                                                          (2H each, d), 7.12-7.32(8H, m)                 7-9   H   H  Ac  I  3 3  syrup 1.12-1.28(2H, m), 1.40-1.56(2H, m),                                           1.91(3H, s), 2.04-2.23(4H, m),                                                3.10(2H, t), 3.17(2H, q), 5.25(1H, br s),                                     7.11-7.32(10H, m)                              __________________________________________________________________________

Reference Example 13-11-Benzoyl-2-(2-phenylethyl)-2-piperidinecarbonitrile ##STR58##

To 200 ml of a solution of lithium diisopropylamide (140 mmol) intetrahydrofuran was added 15 g of solid1-benzoyl-2-piperidinecarbonitrile at -78° C. and the mixture wasstirred for 30 minutes. Then, 100 ml of a solution of 33.2 g ofphenethyl iodide in tetrahydrofuran was added dropwise at -78° C. Aftercompletion of dropwise addition, the temperature of the reaction mixturewas gradually increased to 0° C. The reaction mixture was diluted withwater and the organic layer was separated. The aqueous layer was furtherextracted with ethyl acetate. The pooled organic layer was dried overmagnesium sulfate and filtered and the solvent was distilled off. Thegroup was purified by silica gel column chromatography using ethylacetate-hexane (1:2) as the eluent. The active fraction was concentratedunder reduced pressure and the solid group was recrystallized from ethylacetate-hexane to provide 17.3 g of colorless crystals.

m.p. 65°-67° C. ¹ H-NMR (CDCl₃, δ): 1.52-2.00(4H,m), 2.19(2H,t, J=6 Hz),2.37-2.98(4H,m), 3.29-3.57(2H,m), 7.13-7.56(10H,m)

Elemental analysis: C₂₁ H₂₂ N₂ O. Calcd. C 79.21; H 6.96; N 8.80. FoundC 79.13; H 6.89; N 8.64

The following compounds were synthesized in the same manner as ReferenceExample 6-1.

Reference Example 13-2

1-Benzoyl-2-[2-(3-methoxyphenyl)ethyl]-2-piperidinecarbonitrile

Reference Example 13-3

1-Benzoyl-2-[2-(3,4-dimethoxyphenyl)ethyl]-2-piperidinecarbonitrile

Reference Example 13-4

1-Benzoyl-2-[2-thienylethyl]-2-piperidinecarbonitrile

The structural formulas, physical properties, and NMR spectra of theabove compounds are shown in Table 8.

                                      TABLE 8                                     __________________________________________________________________________                                                       Elemental Analysis         Reference                                                                           Structural               Melting             [Cald./Found)]             Example                                                                             Formula                  Point(°C.)                                                                   NMR (δ ppm, CDCl.sub.3)                                                               C   H   N                  __________________________________________________________________________    13-2                                                                                 ##STR59##               82-84 1.55-1.98(4H, m), 2.19(2H, t,                                                 J=6Hz), 2.36-2.96(4H,                                                         m), 3.27-3.57(2H, m), 3.79(3H, s),                                            6.71-6.85(3H, m), 7.14-7.25(1H, m),                                           7.36-7.56(5H, m)                                                                             ##STR60##                 13-3                                                                                 ##STR61##               oil   1.54-1.99(4H, m), 2.19(2H, t,                                                 J=6Hz), 2.34-2.94(4H,                                                         m), 3.27-3.56(2H, m), 3.85(3H, s),                                            3.87(3H, s), 6.72-6.83(3H, m),                                                7.37-7.58(5H, m)                                                                             ##STR62##                 13-4                                                                                 ##STR63##               oil   1.50-1.97(4H, m), 2.17(2H, t,                                                 J=6Hz), 2.45-2.80(2H,                                                         m), 2.92-3.22(2H, m), 3.29-3.58(2H,                                           m), 6.83-6.87(1H, m), 6.92(1H, dd,                                            J=4,5Hz), 7.13(1H, dd, J=2, 5Hz),                                             7.37-7.58(5H, m)                                                                             ##STR64##                 __________________________________________________________________________

Reference Example 13-5 3,4-Dihydrospiro[naphthalene-2(1H),2'-piperidin]-1-one Hydrochloride ##STR65##

In 250 ml of 1,2-dichloroethane was dissolved 7.64 g of1-benzoyl-2-(2-phenylethyl)-2-piperidinecarbonitrile. To this solutionwas added 8.0 g of aluminum chloride and the mixture was refluxed for 6hours. The reaction mixture was then cooled and poured cautiously into10% aqueous sodium hydroxide and extracted with methylene chloride andwater. The methylene chloride layer was dried over anhydrous sodiumsulfate and filtered and the solvent was distilled off. To the group wasadded 100 ml of methanol and 100 ml of 20% aqueous sodium hydroxide andthe mixture was refluxed for 12 hours. After cooling, methanol wasdistilled off and the group was extracted with methylene chloride andwater. The methylene chloride layer was dried over anhydrous sodiumsulfate and filtered and the solvent was distilled off. The group waspurified by alumina column chromatography using ethyl acetate-hexane(1:2) as the eluent. The active fraction was concentrated under reducedpressure and the group was treated with 6.0 ml of 4N-methanolichydrochloric acid to give a solid. This solid was recrystallized frommethylene chloride to provide 3.0 g of colorless crystals.

m.p. 222°-223° C. ¹ H-NMR (CDCl₃, δ): 1.37-1.85(5H,m), 1.92-2.14(3H,m),2.44(1H,dt,J=7 Hz,5 Hz), 2.76-3.16(4H,m), 7.20-7.52(3H,m),8.29(1H,dd,J=8 Hz,1 Hz)

Elemental analysis: C₁₄ H₁₈ ClNO.H₂ O. Calcd. C 62.33; H 7.47; N 5.19.Found C 62.39; H 7.27; N 5.42

The following compounds were synthesized in the same manner as ReferenceExample 13-5.

Reference Example 13-6

3,4-Dihydro-6-methoxyspiro[naphthalene-2(1H),2'-piperidin]-1-onehydrochloride

Reference Example 13-7

3,4-Dihydro-8-methoxyspiro[naphthalene-2(1H),2'-piperidin]-1-onehydrochloride

Reference Example 13-8

3,4-Dihydro-6,7-dimethoxyspiro[naphthalene-2(1H),2-piperidin]-1-onehydrochloride

Reference Example 13-9

6,7-Dihydrospiro[benzo[b]thiophene-5(4H),2'-piperidin]-4-onehydrochloride

The structural formulas, physical properties, and NMR spectra of theabove compounds are shown in Table 9.

                                      TABLE 9                                     __________________________________________________________________________    Re-                                                Elemental Analysis         ference                    Melting                 [Cald./(Found)]            Example                                                                            Structural Formula    Point(°C.)                                                                    NMR (δppm, CDCl.sub.3)                                                                   C   H   N                  __________________________________________________________________________    13-6                                                                                ##STR66##            249 (decomposed)                                                                     1.31-1.88(6H, m), 1.89-2.10(1H, m),                                           2.16(1H, br s), 2.34-2.50(1H, m),                                             2.74-3.14(4H, m), 3.84(3H, s), 6.66(1H,                                       d, J=3Hz), 6.82(1H, dd, J=9.3Hz),                                             7.99(1H, d, J=9Hz)                                                                              ##STR67##                 13-7                                                                                ##STR68##            255-259 (decomposed)                                                                 1.42-2.21(6H, m), 2.74-2.85(2H, m),                                           3.05-3.19(2H, m), 3.36-3.55(1H, m),                                           3.76-4.00(1H, m), 3.88(3H, s), 6.81(2H,                                       t, J=8Hz), 7.42(1H, t, J=8Hz), 9.06(1H,                                       br s)                                                                                           ##STR69##                 13-8                                                                                ##STR70##            245-248 (decomposed)                                                                 1.33-1.85(5H, m), 1.93-2.10(1H, m),                                           2.35(1H, br s), 2.42(1H, t, J=5Hz),                                           2.50(1H, t, J=5Hz), 2.76-3.35(4H, m),                                         3.92(3H, s), 3.93(3H, s), 6.64(1H, s),                                        7.50(1H, s)                                                                                     ##STR71##                 13-9                                                                                ##STR72##            >280   1.34-1.90(7H, m), 2.02-2.18(1H, m),                                           2.46-2.60(1H, m), 2.75-3.21(4H, m),                                           7.09(1H, d, J=5Hz), 7.37(1H, d,                                                                 ##STR73##                 __________________________________________________________________________

Reference Example 13-103,4-Dihydrospiro[naphthalene-2(1H),2'-piperidin]-1-ol ##STR74##

In 20 ml of methanol was dissolved 0.80 g of3,4-dihydrospiro[naphthalene-2(1H),2'-piperidin]-one and followingaddition of 0.15 g of sodium borohydride in small portions, the mixturewas stirred for 30 minutes. The reaction mixture was then diluted withwater and extracted with methylene chloride. The methylene chloridelayer was dried over anhydrous sodium sulfate and filtered and thesolvent was distilled off. The solid group was recrystallized frommethylene chloride-ether to provide 0.25 g of white crystals.

m.p. 125°-127° C. ¹ H-NMR (CDCl₃, δ): 1.32-1.98(8H,m), 2.28(1H,quint,J=7 Hz), 2.74-2.94(4H,m), 4.37(1H,s), 7.07-7.28(4H,m),7.40-7.52(1H,m)

Elemental analysis: C₁₄ H₁₉ NO. Calcd. C 77.38; H 8.81; N 6.45. Found C77.16; H 8.84; N 7.01.

The following compounds were synthesized in the same manner as ReferenceExample 13-10.

Reference Example 13-11

3,4-Dihydro-6-methoxyspiro[naphthalene-2(1H),2'-piperidin]-1-ol

Reference Example 13-12

3,4-Dihydro-6,7-dimethoxyspiro[naphthalene-2(1H),2-piperidin]-1-olhydrochloride

Reference Example 13-13

6,7-Dihydrospiro[benzo[b]thiophene-5(4H),2'-piperidin]-4-olHydrochloride

The structural formulas, physical properties, and NMR spectra of theabove compounds are shown in Table 10.

                                      TABLE 10                                    __________________________________________________________________________    Re-                                                Elemental Analysis         ference                    Melting                 [Cald./(Found)]            Example                                                                            Structural Formula    Point(°C.)                                                                    NMR (δ ppm, CDCl.sub.3)                                                                  C   H   N                  __________________________________________________________________________    13-11                                                                               ##STR75##            132-134                                                                              1.33-1.87(9H, m), 2.06-2.22(1H, m),                                           2.72-2.89(4H, m), 3.78(3H, s), 4.31(1H,                                       s), 6.64(1H, d, J=3Hz), 6.67(1H, dd,                                          J=9Hz, 3Hz), 7.33(1H, d,                                                                        ##STR76##                 13-12                                                                               ##STR77##            213-216 (decomposed)                                                                 1.36-1.80(8H, m), 2.03-2.24(2H, m),                                           2.74(2H, t, J=7Hz), 2.80-2.90(2H, m),                                         3.84(3H, s), 3.86(3H, s), 4.28(1H, s),                                        6.59(1H, s), 6.95(1H,                                                                           ##STR78##                 13-13                                                                               ##STR79##            215-221 (decomposed)                                                                 1.34-1.90(8H, m), 2.08-2.40(2H, m),                                           2.75-2.90(4H, m), 4.38(1H, s), 7.00(1H,                                       d), 7.12(1H, d)                                                                                 ##STR80##                 __________________________________________________________________________

Reference Example 13-143,4-Dihydrospiro[naphthalene-2(1H),2'-piperidine] Hydrochloride##STR81##

(1) To 200 ml of a solution of 3.36 g of3,4-dihydrospiro[naphthalene-2(1H),2'-piperidin]-1-one in methylenechloride was added 2.6 g of potassium carbonate. Then, 50 ml of asolution of trifluoroacetic anhydride (3.4 ml) in methylene chloride wasadded dropwise at 0° C. and the mixture was stirred for 3 hours. Thisreaction mixture was diluted with water and extracted with methylenechloride. The methylene chloride layer was dried over anhydrousmagnesium sulfate and filtered and the solvent was distilled off. Thegroup was purified by silica gel column chromatography using ethylacetate-hexane (1:2) as the eluent and the active fraction wasconcentrated under reduced pressure. The solid group was recrystallizedfrom ethyl acetate-hexane to provide 4.86 g of1'-trifluoroacetyl-3,4-dihydrospiro[naphthalene-2(1H),2'-piperidin]-1-oneas colorless needles.

m.p. 97°-100° C. ¹ H-NMR (CDCl₃, δ): 1.60-2.25(7H,m), 2.67-3.16(3H,m),3.35-3.53(1H,m), 3.82-3.98(1H,m), 7.16-7.52(3H,m), 8.20(1H,dd,J=8 Hz,1.2Hz)

Elemental analysis: C₁₆ H₁₆ F₃ NO₂. Calcd. C 61.73; H 5.18; N 4.50.Found C 61.47; H 5.20; N 4.40.

(2) In 30 ml of acetic acid was dissolved 4.44 g of1'-trifluoroacetyl-3,4-dihydrospiro[naphthalene-2(1H),2'-piperidin]-1-onefollowed by addition of 0.76 g of 10% palladium-on-carbon, and thecatalytic reduction was carried out at 4 kg/cm² and 80° C. This reactionmixture was poured in water, made basic to 10% aqueous solution ofsodium hydroxide, and extracted with methylene chloride. The methylenechloride layer was dried over anhydrous sodium sulfate and filtered andthe solvent was distilled off. The group was treated with 3.6 ml of4N-methanolic hydrochloric acid to give a solid. This solid wasrecrystallized from methylene chloride-ether to provide 2.51 g of whitecrystals.

m.p. 200°-202° C. ¹ H-NMR (CDCl₃, δ): 1.43-1.80(8H,m), 1.84-2.02(1H,m),2.77(2H,s), 2.84(4H,t,J=5 Hz), 7.10(4H,s)

Elemental analysis: C₁₄ H₂₀ ClN.1/4H₂ O. Calcd. C 69.40; H 8.53; N 5.78.Found C 69.62; H 8.38; N 5.64

Reference Example 13-153,4-Dihydro-6-methoxyspiro[naphthalene-2(1H),2'-piperidine]Hydrochloride ##STR82##

In 30 ml of trifluoroacetic acid was dissolved 6.57 g of3,4-dihydro-6-methoxyspiro[naphthalene-2(1H),2'-piperidin]-1-onefollowed by addition of 8.5 ml of triethylsilane and the mixture wasstirred for 1 hour. This reaction mixture was poured portionwise inwater. To this was added 1N-hydrochloric acid and the mixture was washedwith hexane. The aqueous layer was made basic to 1N-aqueous sodiumhydroxide and extracted with methylene chloride. The methylene chloridelayer was dried over anhydrous sodium sulfate and filtered and thesolvent was distilled off. The group was treated with 7.0 ml of4N-methanolic hydrochloric acid to give a solid. This solid wasrecrystallized from methanol-ether to provide 5.09 g of white crystals.

m.p. 201°-203° C. ¹ H-NMR (CDCl₃, δ): 1.31-2.00(9H,m),2.71(2H,s),2.74-2.88(4H,m), 3.77(3H,m), 6.62-6.73(2H,m), 6.98 (1H,m)

Elemental analysis: C₁₅ H₂₂ ClNO.3/10H₂ O. Calcd. C 66.60; H 8.31; N5.18. Found C 66.65; H 8.46; N 5.03

The following compounds were synthesized in the same manner as ReferenceExample 13-15.

Reference Example 13-16

3,4-Dihydro-6,7-dimethoxyspiro[naphthalene-2(1H),2'-piperidine]hydrochloride

Reference Example 13-17

3,4-Dihydro-8-methoxyspiro[naphthalene-2(1H),2'-piperidine]hydrochloride

Reference Example 13-18

6,7-Dihydrospiro[benzo[b]thiophene-5(4H),2'-piperidine] hydrochloride

The structural formulas, physical properties, and NMR spectra of theabove compounds are shown in Table 11.

                                      TABLE 11                                    __________________________________________________________________________    Re-                                                Elemental Analysis         ference                    Melting                 [Cald./(Found)]            Example                                                                            Structural Formula    Point(°C.)                                                                    NMR (δ ppm, CDCl.sub.3)                                                                  C   H   N                  __________________________________________________________________________    13-16                                                                               ##STR83##            205-208                                                                              1.39-2.00(9H, m), 2.63-2.28(6H, m),                                           3.83(6H, s), 6.55(1H, s), 6.59(1H,                                                              ##STR84##                 13-17                                                                               ##STR85##            239-241                                                                              1.40-1.74(8H, m), 1.81-1.98(1H, m),                                           2.53-2.96(6H, m), 3.81(3H, s), 6.66(1H,                                       d, J=8Hz), 6.73(1H, d, J=8Hz), 7.09(1H,                                       d, J=8Hz)                                                                                       ##STR86##                 13-18                                                                               ##STR87##            212-220                                                                              1.40-1.85(8H, m), 1.92-2.05(1H, m),                                           2.52-2.90(6H, m), 6.72(1H, d), 7.08(1H,                                       d)                                                                                              ##STR88##                 __________________________________________________________________________

Reference Example 143,4-Dihydro-6-ethoxyspiro[naphthalene-2(1H),2'-piperidine] Hydrochloride

1)3,4-Dihydro-6-methoxy-1'-trifluoracetylspiro[naphthalene-2(1H),2'-piperidine]

To a solution of3,4-dihydro-6-methoxyspiro[naphthalene-2(1H),2'-piperidine] (5.0 g) indichloromethane (100 ml) was added pyridine (4.5 ml) and trifluoroaceticanhydride (5.2 ml) and the solution was stirred at 0° C. for 1 hour andat ambient temperature for 2 hours. The water was added to the reactionmixture and extracted with dichloromethane. The dichloromethane phasewas washed with dilute hydrochloric acid and dried with anhydrous sodiumsulfate, filtered, and evaporated. The residue was recrystallized fromhexane to give which crystals (5.2 g).

m.p. 75°-76° C.

2)3,4-Dihydro-6-hydroxy-1'-trifluoracetylspiro[naphthalene-2(1H),2'-piperidine]

To a solution of3,4-dihydro-6-methoxy-1'-trifluoracetylspiro[naphthalne-2(1H),2'-piperidine]in dichloromethane (60 ml) was added ethanetiol (30 ml) and aluminumchloride (3.3 g) under cooling with ice-water. The reaction mixture wasstirred for one hour and poured into ice-water, extracted withdichloromethane, dried and concentrated to give the titled compound.

m.p. 113°-116° C.

3) 3,4-Dihydro-6-ethoxyspiro[naphthalene-2(1H),2'-piperidine]Hydrochloride

To a solution of3,4-dihydro-6-hydroxy-1'-trifluoracetylspiro[naphthalene-2(1H),2'-piperidine]in DMF (5 ml) and sodium hydride (100 mg) was added ethyl iodide (273mg) at 60° C. After stirring at 60° C. for 3 hours the reaction mixturewas partitioned with ethyl acetate/water and the organic phase waswashed with water, dired, and concentrated. The residue was dissolved ina mixture of methanol (50 ml) and 1N aqueous sodium hydroxide (10 ml).The reaction mixture was stirred for 6 hours and concentrated under thereduced pressure. The residue was extracted with ethyl acetate, washedwith water, dried, and evaporated. The residue was treated with 4Nhydrochloricacid to give the hydrochloride salt (184 mg).

¹ H-NMR (CDCl₃, δ): 1.39(3H,t,J=7 Hz), 1.45-1.96(8H,m), 2.69(2H,s),2.72-2.9(4H,m), 3.99(2H,q,J=7 Hz), 6.64-6.70(2H,m), 6.96(1H,d,J=8 Hz)

Reference Example 153,4-Dihydro-6,7-methylenedioxyspiro[naphthalene-2(1H),2'-piperidine]

3,4-Dihydro-6,7-dimethoxyspiro[naphthalene-2(1H),2'-piperidine]hydrochloride (10 mg) was treated with potassium carbonate (10 g) andbenzyl bromide (4 ml) in DMF (300 ml) at 60° C. for 2 hours. Thereaction product was extracted with ethyl acetate-water, washed withwater, dried, and concentrated. Purification with silica gel columnchromatography (eluent; ethyl acetate) gave3,4-dihydro-6,7-dimethoxy-1'-benzylspiro[naphthalene-2(1H),2'-piperidine](10.8 g) which was dissolved in hydrobromic acid (33 ml) at 60° C. Afterbeing refluxed for 1.5 hr, the reaction mixture was poured into waterand neutralized with sodium bicarbonate followed by extraction withethyl acetate. The extract was washed with water, dried, andconcentrated. The residue was crystallized from hexane to give3,4-dihydro-6,7-hydroxy-1'-benzylspiro[naphthalene-2(1H),2'-piperidine](5.92 g).

m.p. 122°-124° C.

To a solution of3,4-dihydro-6,7-hydroxy-1'-benzylspiro[naphthalene-2(1H),2'-piperidine](390 mg) in DMF (5 ml) was added sodium hydride (144 mg). Dibromomethane (0.85 g) was added at 60° C. and the the reaction mixture washeated at 60° C. for 1 hr. The reaction mixture was poured into waterand extracted with ethyl acetate. The organic phase was washed withwater, dried and concentrated under the reduced pressure. Purificationwith silica gel chromatography gave3,4-dihydro-6,7-dihydro-6,7-hydroxy-1'-benzylspiro[naphthalene-2(1H),2'-piperidine].

¹ H-NMR (CDCl₃, δ): 1.37-1.65(6H,m), 1.70-1.86(1H,m), 1.88-2.07(1H,m),2.47-2.96(6H,m), 3.47-3.73(2H,m), 5.87(2H,m), 6.56(1H,m), 6.57(1H,m),7.14-7.40(5H,m)

The suspension of3,4-dihydro-6,7-hydroxy-1'-benzylspiro[naphthalene-2(1H),2'-piperidine](164 mg) and 10% Pd-carbon (150 mg) in ethanol (10 ml) and conc.hydrochloric acid (0.3 ml) was hydrogenated under atmospheric pressureat ambient temperature for 18 hr. The catalysis was filtered off and thefiltrate was concentrated. The residue was neutralized with sodiumbicarbonate and extracted with ethyl acetate, The organic phase waswashed with water, dried, and concentrated to give the product (90 mg).

¹ H-NMR (CDCl₃, δ): 1.42-1.98(9H,m), 2.64-2.87(6H,m), 5.87(2H,s),6.53(1H,s), 6.57(1H,s)

Reference Example 163,4-Dihydro-6,7-diethoxyspiro[naphthalene-2(1H),2'-piperidine]Hydrochloride

To a solution of3,4-dihydro-6,7-dihydroxy-1'-benzylspiro[naphthalene-2(1H),2'-piperidine](970 mg) in DMF (10 ml) was added sodium hydride (691 mg) followed byethyliodide (0.48 ml). After stirring for 3 hours at ambienttemperature, the reaction mixture was poured into water and extractedwith ethyl acetate. The extract was washed with water, dried, andevaporated under the reduced pressure. The residue was purified bysilica gel column chromatography (eluent; ethyl acetate) to give an oilwhich was subjected to a catalytic hydrogenation reaction to give thetitled compound as a hydrochloride salt.

Elemental analysis: C₁₈ H₂₈ ClNO₂. Calcd. C 66.34; H 8.66; N 4.30. FoundC 66.22; H 9.15; N 4.03

Reference Example 173,4-Dihydro-6-methoxy-7-nitrospiro[naphthalene-2(1H),2'-piperidine]Hydrochloride ##STR89##

(1) 6.0 g of1'-trifluoroacetyl-3,4-dihydro-6-methoxyspiro[naphthalene-2(1H),2'-piperidine]was dissolved in 150 ml of chloroform. After 1.5 g of ammonium nitratewas suspended in this solution, 9 ml of trifluoroacetic anhydride wasadded, followed by overnight stirring at room temperature. After waterwas added, the reaction mixture was extracted with methylene chloride.The extract was dried over anhydrous sodium sulfate and filtered, afterwhich the solvent was distilled off. The residue was purified by silicagel column chromatography to yield 1.4 g of1'-trifluoroacetyl-3,4-dihydro-6-methoxy-7-nitrospiro[naphthalene-2(1H),2'-piperidine]and 0.457 g of1'-trifluoroacetyl-3,4-dihydro-6-methoxy-5-nitrospiro[naphthalene-2(1H),2'-piperidine].

1'-Trifluoroacetyl-3,4-dihydro-6-methoxy-7-nitrospiro[naphthalene-2(1H),2'-piperidine]

m.p. 105°-107° C.

1'-Trifluoroacetyl-3,4-dihydro-6-methoxy-5-nitrospiro[naphthalene-2(1H),2'-piperidine]

m.p. 128°-130° C.

(2) 0.5 g of1'-trifluoroacetyl-3,4-dihydro-6-methoxy-7-nitrospiro[naphthalene-2(1H),2'-piperidine]as obtained in term (2) above was dissolved in 50 ml of methanol. Tothis solution, 0.221 g of potassium carbonate and 5 ml of water wereadded, followed by stirring at room temperature for 15 hours. Afterreaction mixture extraction with ethyl acetate, the extract was driedover anhydrous sodium sulfate and filtered, after which the solvent wasdistilled off. The residue was treated with a 4N hydrochloric acid-ethylacetate solution to yield3,4-dihydro-6-methoxy-7-nitrospiro[naphthalene-2(1H),2'-piperidine]hydrochlorideas a noncrystalline powder.

¹ H-NMR (CDCl₃, δ): 1.45-2.00(8H,m), 2.73(2H,s), 2.80-2.95(4H,m),3.91(3H,s), 6.81(1H,s), 7.63(1H,s)

Reference Example 183,4-Dihydro-6-methoxy-5-nitrospiro[naphthalene-2(1H),2'-piperidine]Hydrochloride ##STR90##

1'-Trifluoroacetyl-3,4-dihydro-6-methoxy-5-nitrospiro[naphthalene-2(1H),2'-piperidine]as obtained in Reference Example 17 was treated in the same manner toyield the title compound as a noncrystalline powder.

¹ H-NMR (free base, CDCl₃, δ): 1.44-1.75(7H,m), 1.89-1.96(1H,m),2.71-2.84(6H,m), 3.85(3H,s), 6.83(1H,d,J=9 Hz), 7.13(1H,d,J=9 Hz)

Reference Example 197-Acetyl-3,4-dihydro-6-methoxyspiro[naphthalene-2(1H),2'-piperidine]##STR91##

(1) 2.94 g of1'-trifluoroacetyl-3,4-dihydro-6-methoxyspiro[naphthalene-2(1H),2'-piperidine]as obtained in Example 22-(1) was dissolved in 30 ml of carbondisulfide. To this solution, 0.85 ml of acetic anhydride was added underice cooling conditions. After 2.4 g of aluminum chloride was added, themixture was stirred at room temperature overnight. The reaction mixturewas then added to ice water and extract with ethyl acetate. Theextracted was dried over anhydrous sodium sulfate and filtered, afterwhich the solvent was distilled off. The residue was purified by silicagel column chromatography to yield a crude crystal, which was thenrecrystallized from ethyl acetate-hexane to yield 0.21 g of7-acetyl-1'-trifluoroacetyl-3,4-dihydro-6-methoxyspiro[naphthalene-2(1H),2'-piperidine].

m.p. 156°-157° C.

Reference Example 20-1 2-Chloroacetylamino-2-hydroxymethyltetralin

To a suspension of 2-aminotetralin-2-carboxylic acid (500 mg, 2.6 mmol)in THF (10 ml), lithium aluminum hydride (250 mg, 6.5 mmol) was added,while the suspension was stirred at room temperature, followed byfurther stirring at constant temperature for 2 hours. To this mixture, a1N aqueous sodium hydroxide solution was added. After the precipitatewas filtered out, the mother liquor was washed with saturated saline anddried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure to yield an almost pure aminoalcohol (420 mg, 85%) as acolorless syrup. The alcohol (420 mg, 2.2 mmol) was then dissolved in anethyl acetate (10 ml)-saturated sodium carbonate solution (10 ml). Tothis solution, chloroacetyl chloride (340 mg, 3 mmol) was added drop bydrop, while the solution was vigorously stirred under ice coolingconditions. Five minutes later, the organic layer was separated, washedwith saturated saline and dried over anhydrous sodium sulfate. After thesolvent was distilled off under reduced pressure, the residue wassubjected to silica gel column chromatography for elution withhexane-ethyl acetate (1:1) to yield 400 mg (72%) of the title compound.

Reference Example 20-2

2-(Chloroacetyl)amino-2-hydroxymethyl-6-methoxytetralin was synthesizedin the same manner as in Reference Example 20-1.

Reference Example 20-3

2-(Chloroacetyl)amino-2-hydroxymethyl-7-methoxytetralin was synthesizedin the same manner as in Reference Example 20-1.

Reference Example 20-4

2-(Chloroacetyl)amino-6,7-dimethoxy-2-(hydroxymethyl)tetralin wassynthesized in the same manner as in Reference Example 20-1.

Table 12 shows the structural formulas, physical properties and ¹ H-NMRspectra of these compounds.

                                      TABLE 12                                    __________________________________________________________________________    Reference                    Melting                                          Example                                                                             Structural Formula     Point(°C.)                                                                   .sup.1 H-NMR (ppm, CDCl.sub.3)             __________________________________________________________________________    20-1                                                                                 ##STR92##             oil   1.97(1H, ddd, J=13.0, 8.8, 7.0Hz),                                            2.26(1H, ddd, J=13.0, 7.9, 5.8Hz),                                            2.73-3.09(4H, m), 3.81(2H, s),                                                3.98(2H, s), 4.04-4.45(1H, br),                                               6.60(1H, br s), 7.05-7.19(4H, m)           20-2                                                                                 ##STR93##             oil   1.95(1H, m), 2.26(1H, m),                                                     2.70-3.00(4H, m), 3.78(3H, s),                                                3.80(2H, s), 3.98(2H, s), 6.60(1H, br                                         s), 6.64-6.75(2H, m), 7.00(1H, d,                                             J=8.4Hz)                                   20-3                                                                                 ##STR94##             oil   1.92(1H, m), 2.25(1H, m),                                                     2.65-3.08(4H, m), 3.76(3H, s),                                                3.79(2H, d, J=4.6Hz), 3.97(2H, s),                                            4.23(1H, br s), 6.60 (1H, s), 6.61(1H,                                        s), 6.73(1H, dd, J=8.4, 2.6Hz),                                               7.03(1H, ) d, J=8.4Hz)                     20-4                                                                                 ##STR95##             210-212                                                                             1.62(1H, m), 2.30(1H, m),                                                     2.55-2.98(4H, m), 3.58(2H, br s),                                             3.70(6H, s), 3.97(2H, q, J=17.6,                                              12.4Hz), 4.82(1H, brt, J=6Hz), 6.60,                                          6.64(1H, each, s), 7.59(1H, br s)                                             (DMSO-d.sub.6)                             __________________________________________________________________________

Reference Example 21-1 Spiro[tetralin-2,3'-morpholine-5'-one]

To a suspension of sodium hydride (120 mg, 5 mmol, 60% oil, washed withhexane) in DMF (3 ml), a solution of2-chloroacetylamino-2-hydroxymethyltetralin (400 mg, 1.6 mmol) in DMF (3ml) was added drop by drop, while the suspension was stirred under icecooling conditions. After cooling to room temperature, the mixture wasstirred for 3 hours at constant temperature. After a large amount ofwater was added, the mixture was extracted with ethyl acetate. Theorganic layer was washed with water several times, washed with saturatedsaline and dried over anhydrous sodium sulfate. After the solvent wasdistilled off under reduced pressure, the residue was subjected tosilica gel column chromatography for elution with hexane-ethyl acetate(1:1-1:2) to yield 150 mg (43%) of the title compound as a whitecrystal.

Reference Example 21-2 6-Methoxyspiro[tetralin-2,3'-morpholine]-5'-one

To a solution of 2-chloroacetylamino-2-hydroxy-6-methoxytetralin (450mg, 1.6 mmol) in THF (15 ml), 60% oily sodium hydride (200 mg, 5.0 mmol)was added, while the solution was stirred under ice cooling conditions.After cooling to room temperature, the mixture was stirred for 3 hoursat constant temperature. After a saturated aqueous solution of ammoniumchloride was added, the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated saline and dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure toyield about 400 mg (almost 100%) of the title compound as a crudecrystal, a portion of which was then recrystallized fromchloroform-isopropyl ether.

Reference Example 21-3

7-Methoxyspiro[tetraline-2,3'-morpholine]-5'-one was synthesized in thesame manner as in Reference Example 21-2.

Reference Example 21-4

6,7-Dimethoxyspiro[tetralin-2,3'-morpholine]-5'-one was synthesized inthe same manner as in Reference Example 21-2.

Table 13 shows the structural formulas, physical properties and ¹ H-NMRspectra of these compounds.

                                      TABLE 13                                    __________________________________________________________________________    Reference                   Melting                                           Example                                                                             Structural Formula    Point(°C.)                                                                   .sup.1 H-NMR (ppm, CDCl.sub.3)              __________________________________________________________________________    21-1                                                                                 ##STR96##            164-166                                                                             1.80-2.15(2H, m), 2.73-3.07(4H, m),                                           3.69(2H, s), 4.20(2H, s), 6.32(1H, br                                         s), 7.03-7.20(4H, m)                        21-2                                                                                 ##STR97##            173-174                                                                             1.78-2.15(2H, m), 2.65-2.95(4H, m),                                           3.68(2H, s), 3.78(3H, s), 4.20(2H, s),                                        6.10(1H, br s), 6.63-6.76(2H, m), 6.98                                        (1H, d, J=8.4Hz)                            21-3                                                                                 ##STR98##            144-148                                                                             1.78-2.15(2H, m), 2.69-3.01(4H, m),                                           3.69(2H, s), 3.78(3H, s), 4.21(2H, s),                                        6.00(1H, br s), 6.59(1H, d, J=2.8Hz),                                         6.76 (1H, dd, J=8.4, 7.8Hz), 7.05(1H,                                         d, J=8.4Hz)                                 21-4                                                                                 ##STR99##            202-204                                                                             1.75-1.95(1H, m), 1.96-2.15(1H, m),                                           2.65-2.95(4H, m), 3.69(2H, s), 3.84,                                          3.86(3H, each, s), 4.21(2H, s), 6.03                                          (1H, br s), 6.57, 6.01(1H, each,            __________________________________________________________________________                                      s)                                      

Reference Example 22-1 Spiro[tetralin-2,3'-morpholine] Hydrochloride

To a solution of spiro[tetralin-2,3'-morpholine]-5'-one (22 mg, 0.1mmol) in THF (2 ml), lithium aluminum hydride (12 mg, 0.3 mmol) wasadded, while the solution was stirred under ice cooling conditions.After cooling to room temperature, the mixture was stirred for 1 hour atconstant temperature. After further stirring at 60° C. for 3 hours, a 1Naqueous sodium hydroxide solution was added; the precipitate wasfiltered out. The mother liquor was washed with saturated saline anddried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure. The obtained residue was subjected to silica gelcolumn chromatography for elution with ethyl acetate-methanol (1:0-9:1).After concentration, the organic layer was dissolved inwater-chloroform; the chloroform layer was dried and concentrated underreduced pressure. The obtained residue was dissolved in ethyl acetate.To this solution, a 4N hydrogen chloride-ethyl acetate solution wasadded. The mixture was concentrated under reduced pressure andcrystallized with isopropyl ether to yield 12 mg (49%) of the titlecompound.

Reference Example 22-2

6-Methoxyspiro[tetralin-2,3'-morpholine]hydrochloride was synthesized inthe same manner as in Reference Example 22-1.

Reference Example 22-3

7-Methoxyspiro[tetralin-2,3'-morpholine]hydrochloride was synthesized inthe same manner as in Reference Example 22-1.

Reference Example 22-4

6,7-Dimethoxyspiro[tetralin-2,3'-morpholine]hydrochloride wassynthesized in the same manner as in Reference Example 22-1.

Table 14 and 15 show the structural formulae, physical properties and ¹H-NMR spectra of these compounds.

                                      TABLE 14                                    __________________________________________________________________________    Reference                   Melting                                           Example                                                                             Structural Formula    Point(°C.)                                                                   .sup.1 H-NMR (ppm, CDCl.sub.3)              __________________________________________________________________________    22-1                                                                                 ##STR100##           164-166                                                                             1.70-1.90(2H, m), 1.91-2.05(1H, m),                                           2.70-2.93(4H, m), 2.94(2H, t, J=4.4Hz),                                       3.52(2H, s), 3.71(2H, t, J=4.8Hz),                                            7.00-7.12(4H, m)                            22-2                                                                                 ##STR101##           212-215                                                                             1.68-1.85(1H, m), 1.86-2.03(2H, m),                                           2.65-2.90(4H, m), 2.93(2H, t, J=4.6Hz),                                       3.51(2H, s), 3.71(2H, t, J=4.8Hz),                                            3.77(3H, s), 6.63-6.74(2H, m), 7.01(1H,                                       d, J=8.4Hz)                                 __________________________________________________________________________

                                      TABLE 15                                    __________________________________________________________________________    Reference                   Melting                                           Example                                                                             Structual Formula     Point (°C.)                                                                  .sup.1 HNMR (ppm, CDCl.sub.3)               __________________________________________________________________________    22-3                                                                                 ##STR102##           230-235                                                                             1.65-2.04(3H, m), 2.65-2.87(4H, m),                                           2.93(2H, t, J=5, 6Hz), 3.51(2H, s),                                           3.70(2H, t, J=5.4Hz), 3.77(3H, s),                                            6.63(1H, d, J=2.6Hz), 6.72(1H, dd,                                            J=8.2, 2.8Hz), 7.03(1H, d, J=8.2Hz)         22-4                                                                                 ##STR103##           212-215                                                                             1.68-1.84(1H, m), 1.85-2.07(2H, m),                                           2.63-2.90(4H, m), 2.95(2H, t, J=4.8Hz),                                       3.52(2H, s), 3.72(2H, t, J=5.2Hz),                                            3.84(6H, s), 6.56, 6.62(1H, each,           __________________________________________________________________________                                      s)                                      

Reference Example 233,4-Dihydro-6,7-dimethoxy-4'-methylspiro[naphthalene-2(1H),2'-piperazine]Dihydrochloride

(1) Ethyl2-[(N-benzyloxycarbonyl-N-methylamino)acetylamino]-1,2,3,4-tetrahydro-6,7-dimethoxynaphthalene-2-carboxylate

To a solution of ethyl2-amino-1,2,3,4-tetrahydro-6,7-dimethoxynaphthalene-2-carboxylate (430mg, 1.5 mmol), N-benzyloxycarbonylsarcosine (357 mg, 1.6 mmol), and1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride indichloromethane (5 ml) was added triethylamine (160 mg, 1.6 mmol) understirring at 0° C. After stirring for 2 hr, the reaction mixture wasconcentrated in vacuo and the residue was dissolved in ethyl acetate.The solution was washed with 1N hydrochloric acid, sat. sodiumbicarbonate, sat. sodium chloride, dried, and evaporated. The residuewas purified with silica gel column chromatography [eluent; hexane-ethylacetate (1:1 to 1:2)] to give the titled compound (550 mg, 74%).

¹ H-NMR (CDCl₃, δ): 1.25(3H,t), 2.05-2.17(1H,m), 2.38-3.00(7H,m),3.22(1H,d), 3.75-3.90(8H,m), 4.20(2H,q), 5.02(2H,s), 6.37-6.60(3H,m),7.20-7.39(5H,m)

(2)3,4-Dihydro-6,7-dimethoxy-4'-methylspiro[naphthalene-2(1H),2'-piperidine]-3',6'-dione

A solution of ethyl2-[(N-benzyloxycarbonyl-N-methylamino)acetylamino]-1,2,3,4-tetrahydro-6,7-dimethoxynaphthalene-2-carboxylate(550 mg, 1.1 mmol) in ethanol (20 ml) was hydrogenated in the presenceof 10% Pd-carbon (250 mg) for 6 hr. The catalyst was filtered off andthe filtrate was concentrated in vacuo. The residue was dissolved in 1Nsodium hydroxide (2 ml) and THF (10 ml) and heated at 80° C. for 17 hr.The reaction mixture was concentrated in vacuo and the residue wasdissolved in ethyl acetate. The solution was washed with water, and sat.sodium chloride, dried, and concentrated in vacuo. The residue wasrecrystallized from chloroform-isopropylether to give the titledcompound (150 mg).

m.p. 168°-169° C.

(3)3,4-Dihydro-6,7-dimethoxy-4'-methylspiro[naphthalene-2(1H),2'-piperazine]

To a suspension of lithium aluminum hydride (114 mg, 3 mmol) andaluminum chloride (400 mg, 3 mmol) in ether (4 ml) was added thesuspension of3,4-dihydro-6,7-dimethoxy-4'-methylspiro[naphthalene-2(1H),2'-piperazine]-3',6'-dione(50 mg, 0.16 mmol) in ether (2 ml). The reaction mixture was stirred atambient temperature for 45 min and treated with 1N sodium hydroxide. Theprecipitate was filtered and washed with 1N sodium hydroxide andchloroform. The filtrate was washed with sat. sodium chloride, dried,and concentrated to give the titled compound (42 mg, 86%). A portion wasdissolved in ethyl acetate and treated with 4N hydrochloric acid inethyl acetate. Concentration under reduced pressure followed by additionof isopropylether gave a powder.

¹ H-NMR (CDCl₃, δ): 1.90-2.05(1H,m), 2.18-2.35(1H,m), 2.69(1H,dd),2.80-2.94(2H,m), 3.06(3H,s), 3.58(1H,d), 3.85,3.86(3H,each s),4.04(2H,ABq), 6.11(1H,br s), 6.53,6.61(1H,each s)

Reference Example 24(R)-(+)-3,4-Dihydro-6-methoxyspiro[naphthalene-2(1H),2'-piperidine]Hydrochloride ##STR104##

After conversion into a free base, 1 g of3,4-dihydro-6-methoxy-spiro[naphthalene-2(1H),2'-piperidine]hydrochloride was dissolved in methanol. To this solution, a methanolsolution of 0.867 g of (S)-(+)-10-camphorsulfonic acid was added,followed by concentration under reduced pressure. After the residue wasdissolved in 10 ml of methanol, 20 ml of isopropyl ether was added; themixture was kept standing at room temperature for 5 hours. The resultingcrystal was collected by filtration and twice recrystallized frommethanol-isopropyl ether to yield 0.2 g of a crystal. After conversioninto a free base, this crystal was treated with a 4N-hydrochloricacid-ethyl acetate solution to yield 0.1 g of(R)-(+)-3,4-dihydro-6-methoxyspiro[naphthalene-2(1H),2'-piperidine]hydrochloride as a white crystal. Optical purity was determined by highperformance liquid chromatography using an optical isomer separationcolumn (CHIRALCEL OB-H, produced by Daicel Chemical Industries, Ltd.).

Optical purity: Over 99.7% ee. Melting point: 152°-155° C. Opticalrotation: [α]_(D) ²⁷ =+3.44

Reference Example 25(S)-(-)-3,4-Dihydro-6-methoxyspiro[naphthalene-2(1H),2'-piperidine]Hydrochloride ##STR105##

The mother liquors for recrystallization of the (+)-configuration inReference Example 24 were combined and concentrated under reducedpressure. After conversion into a free base, the residue was dissolvedin methanol. To this solution, a methanol solution of 0.7 g of(R)-(-)-10-camphorsulfonic acid was added, followed by concentrationunder reduced pressure. The residue was treated in the same manner as inExample 25 to yield 0.09 g of(S)-(-)-3,4-dihydro-6-methoxyspiro[naphthalene-2(1H),2'-piperidine]hydrochloride as a white crystal.

Optical purity: 97.1% ee. Melting point: 155°-160° C.

Reference Example 26(+)-3,4-Dihydro-6,7-dimethoxyspiro[naphthalene-2(1H),2'-piperidine]-1-oneHydrochloride ##STR106##

After conversion into a free base, 10 g of3,4-dihydro-6,7-dimethoxyspiro[naphthalene-2(1H),2'-piperidine]-1-onehydrochloride was dissolved in 700 ml of methanol. To this solution,12.07 g of (2S,3S)-(+)-0,0'-dibenzoyltartaric acid monohydride wasadded. After the mixture was kept standing at room temperature for 3days, the resulting crystal was collected by filtration. Afterconversion into a free base, this crystal was treated with a4N-hydrochloric acid-ethyl acetate solution to yield 1.84 g of(+)-3,4-dihydro-6,7-dimethoxyspiro[naphthalene-2(1H),2'-piperidine]-1-onehydrochloride as a white crystal.

Optical purity: Over 99.9% ee. Melting point : 251°-254° C. Opticalrotation: [α]_(D) ²⁶ =+41.22

Reference Example 27(-)-3,4-Dihydro-6,7-dimethoxyspiro[naphthalene-2(1H),2'-piperidine]-1-oneHydrochloride

The mother liquors for recrystallization of the (+)-configuration inReference Example 26 were combined and concentrated under reducedpressure. After conversion into a free base, the residue was dissolvedin methanol. Using (2R,3R)-(-)-0,0'-dibenzoyltartaric acid monohydride,the solution was treated in the same manner as in Example 27 to yield2.04 g of(-)-3,4-dihydro-6,7-dimethoxyspiro[naphthalene-2(1H),2'-piperidine]-1-onehydrochloride as a white crystal.

Optical purity: Over 99.9% ee. Melting point: 250°-252° C. Opticalrotation: [α]_(D) ²⁶ =-41.41

Reference Example 28(-)-3,4-Dihydro-6,7-dimethoxyspiro[naphthalene-2(1H),2'-piperidine]Hydrochloride

(+)-3,4-dihydro-6,7-dimethoxyspiro[naphthalene-2(1H),2'-piperidine]-1-onehydrochloride as obtained in Example 27 was treated in the sammer as inReference Example 13-10. ##STR107## to yield(-)-3,4-dihydro-6,7-dimethoxyspiro[naphthalene-2(1H),2'-piperidine]hydrochloride.

Melting point: 165°-167° C. Optical rotation: [α]_(D) ²⁶ =-1.92

Reference Example 29(+)-3,4-Dihydro-6,7-dimethoxyspiro[naphthalene-2(1H),2'-piperidine]Hydrochloride

Melting point: 165°-167° C. Optical rotation: [α]_(D) ²⁶ =+1.80

Reference Example 30

1-Benzoylhexahydro-2-(2-phenylethyl)-1H-azepine-2-carbonitrile wasobtained by the same procedure as Reference Example 13-1. ##STR108##

Melting point: 116°-118° C. ¹ H-NMR (CDCl₃, δ): 1.25-1.76(3H,m),1.80-3.23(10H,m), 3.51-3.67(1H,m),7.08-7.50(10H,m).

Reference Example 31

1,3,4,5,6,7,3',4'-Octahydrospiro[2H-azepine-2,2'(1H)-naphthalene]-1'-onehydrochloride was obtained by the same procedure as Reference Example13-5. ##STR109##

Melting point: 208°-210° C. ¹ -NMR (CDCl₃, δ): 1.20-1.84(7H,m),1.87-2.30(4H,m), 2.55-2.71(1H,m), 2.93-3.08(3H,m), 7.21(1H,d,J=8 Hz),7.32(1H,d,J=8 Hz), 7.46(1H,dt,J=8.2 Hz), 8.05(1H,dd,J=8.2 Hz).

Reference Example 32

1,3,4,5,6,7,1',2',3',4'-Decahydrospiro[2H-azepine-2,2'(1H)-naphthalene]hydrochloridewas obtained by the same procedure as Reference Example 13-10 or 13-14.##STR110##

Melting point: 191°-194° C. ¹ H-NMR (CDCl₃, δ): 1.08-1.92(11H,m),2.60-2.98(6H,m), 7.01-7.13(4H,m).

WORKING EXAMPLES Example I-11-(5-Amino-4,4-diphenylpentyl)-4-phenylpiperidine

To a solution of 1-(5-formylamino-4,4-diphenylpentyl)-4-phenylpiperidine(2.07 g) in methanol (50 ml) was added 1N-sodium hydroxide (30 ml) andthe mixture was refluxed overnight. This reaction mixture wasconcentrated to dryness and the group was extracted using methylenechloride and water. The organic layer was washed with water, dried overanhydrous sodium sulfate, and concentrated to dryness to provide thetitle compound (1.94 g) as yellow powder.

The compounds of Examples I-2 through I-4 were synthesized in the samemanner as Example I-1.

Example I-2

3,4-Dihydro-6-methoxy-1'-(5-amino-4,4-diphenylpentyl)spiro[naphthalene-2(1H),2'-piperidine]

Example I-3

1-[5-Amino-4-(4-methoxyphenyl)-4-phenylpentyl]-4-phenylpiperidine

Example I-4

1-[5-Amino-4,4-bis(4-chlorophenyl)pentyl]-4-(4-fluorophenyl)piperadine

Example I-53,4-Dihydro-6-methoxy-1'-(6-amino-4,4-diphenylhexyl)spiro[naphthalene-2(1H),2'-piperidine]

To a solution of3,4-dihydro-6-methoxy-1'-(5-cyano-4,4-diphenylpentyl)spiro[naphthalene-2(1H),2'-piperidine](0.6 g) in tetrahydrofuran (15 ml) was added lithium aluminum hydride(95 mg) portionwise under ice-cooling and stirring. After completion ofdropwise addition, the mixture was heated at 60° C. for 6 hours. To thisreaction mixture were serially added water (0.25 ml), 15% sodiumhydroxide solution (0.75 ml) and water (0.25 ml) under ice-cooling andstirring and the precipitate which separated out was filtered off. Thefiltrate was washed with saturated aqueous solution of sodium chloride,dried over anhydrous sodium sulfate, and concentrated to dryness toprovide the title compound (0.54 g) as light-yellow syrup.

The compound of Example I-6 was synthesized in the same manner asExample I-5.

Example I-63,4-Dihydro-6,7-dimethoxy-1'-(7-amino-4,4-diphenylheptyl)spiro[naphthalene-2(1H),2'-piperidine]

The structural formulae, physical properties, and NMR spectra of theabove compounds are shown in Table 16.

                                      TABLE 16                                    __________________________________________________________________________     ##STR111##                                                                                                      Melting                                    Example                                                                            X   Y  R.sub.1            m n Point (°C.)                                                                  .sup.1 HNMR (δ.sub.ppm,                                                 CDCl.sub.3)                          __________________________________________________________________________    I-1  H   H                                                                                 ##STR112##        1 3 syrup 1.20-1.35(2H, m), 1.65-2.00(8H,                                               m), 2.10-2.20 (2H, m), 2.30(2H,                                               t), 2.35-2.50(1H, m), 2.90 (2H,                                               d), 3.35(2H, s), 7.10-7.35(15H,                                               m)                                   I-2  H   H                                                                                 ##STR113##        1 3 syrup 1.05-2.80(22H, m), 3.30(2H, s),                                               3.76(3H, s), 6.60-6.72(2H, m),                                                6.96(1H, d), 7.13-7.35 (10H, m)      I-3  4-MeO                                                                             H                                                                                 ##STR114##        1 3 syrup                                      I-4  4-Cl                                                                              4-Cl                                                                              ##STR115##        1 3 syrup 1.10-1.30(2H, m), 2.02-2.22(2H,                                               m), 2.37(2H, t), 2.50(4H, t),                                                 3.09(4H, t), 6.80-7.30(12H, m)       I-5  H   H                                                                                 ##STR116##        2 3 syrup 1.05-1.25(2H, m), 1.38-2.80(22H,                                              m), 3.76(3H, s), 6.61-6.71(2H,                                                m), 6.95(1H, d), 7.10-7.30 (10H,                                              m)                                   I-6  H   H                                                                                 ##STR117##        3 3 syrup 1.03-1.21(4H, m), 1.30-2.80(22H,                                              m), 3.82, 3.83 (3H each, s),                                                  6.55, 6.57(1H each, s),                                                       7.10-7.30 (10H,                      __________________________________________________________________________                                             m)                               

Example II-1 1-(N,N-Dimethylamino)-4,4-diphenyl-5-(formylamino)pentane

A mixture of 5-formylamino-1-iodo-4,4-diphenylpentane (8.5 g),dimethylamine hydrochloride (17.63 g), triethylamine (30.1 ml), andpotassium carbonate (3 g) was heated in acetonitrile (250 ml) at 60° C.for 2 hours. This reaction mixture was concentrated to dryness and thegroup was extracted using ethyl acetate and water. The organic layer waswashed with saturated aqueous solution of sodium chloride, dried overanhydrous sodium sulfate, and concentrated to dryness. The group wascrystallized from ethyl acetate-isopropyl ether to provide the titlecompound (4.5 g) as white powder.

The compounds of Examples II-2 through II-10, II-12 through II-16, II-25through II-29, II-31, II-34 through II-36, and II-40 through II-68 wererespectively synthesized in the same manner as Example II-1.

Example II-2

1-(N-Benzyl-N-methylamino)-4,4-diphenyl-5-(formylamino)pentanehydrochloride

Example II-3

4,4-Diphenyl-5-formylamino-1-(morpholino)pentane hydrochloride

Example II-4

4,4-Diphenyl-5-formylamino-1-(2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl)pentanehydrochloride

Example II-5

4,4-Diphenyl-5-formylamino-1-(4-phenylpiperidino)pentane hydrochloride

Example II-6

1-[4-(4-Fluorophenyl)piperazin-1-yl]-5-formylamino-4,4-diphenylpentanedihydrochloride

Example II-7

3,4-Dihydro-6-methoxy-1'-(5-formylamino-4,4-diphenylpentyl)spiro[naphthalene-2(1H),2'-piperidine]dihydrochloride

Example II-8

1-Benzylamino-4,4-diphenyl-5-(tosylamino)pentane hydrochloride

Example II-9

1-(N-Benzyl-N-methylamino)-4,4-diphenyl-5-(tosylamino)pentanehydrochloride

Example II-10

4,4-Diphenyl-1-(3-nitrobenzylamino)-5-(tosylamino)pentane hydrochloride

Example II-12

4,4-Diphenyl-1-[3-(methoxycarbonyl)benzylamino]-5-(tosylamino)pentanehydrochloride

Example II-13

4,4-Diphenyl-1-(2-picolylamino)-5-(tosylamino)pentane dihydrochloride

Example II-14

4,4-Diphenyl-1-(1-hexamethyleneimino)-5-(tosylamino)pentanehydrochloride

Example II-15

4,4-Diphenyl-1-(4-phenylpiperazin-1-yl)-5-(tosylamino)pentane

Example II-16

4,4-Diphenyl-1-[4-(2-methoxyphenyl)piperazin-1-yl]-5-(tosylamino)pentanehydrochloride

Example II-25

4-(4-Chlorophenyl)-5-formylamino-4-phenyl-1-(4-phenylpiperidino)pentanehydrochloride

Example II-26

4-(4-Chlorophenyl)-5-formylamino-4-phenyl-1-(4-phenylpiperazin-1-yl)pentanedihydrochloride

Example II-27

4-(4-Chlorophenyl)-1-[4-(4-fluorophenyl)piperazin-1-yl]-5-formylamino-4-phenylpentanedihydrochloride

Example II-28

4-(4-Chlorophenyl)-1-[4-(diphenylmethyl)piperazin-1-yl]-5-formylamino-4-phenylpentane

Example II-29

5-Formylamino-4-(4-methoxyphenyl)-4-phenyl-1-(4-phenylpiperidino)pentanehydrochloride

Example II-31

4,4-Bis(4-chlorophenyl)-1-[4-(4-fluorophenyl)piperazin-1-yl]-5-(formylamino)pentanedihydrochloride

Example II-34

1-[4-(4-Fluorophenyl)piperazin-1-yl]-6-formylamino-5,5-diphenylhexanedihydrochloride

Example II-35

1-[4-(4-Fluorophenyl)piperazin-1-yl]-6-formylamino-4,4-diphenylhexanedihydrochloride

Example II-36

4,4-Diphenyl-1-(4-phenylpiperidino)-6-(tosylamino)hexane hydrochloride

Example II-40

7-Acetylamino-4,4-diphenyl-1-[3-(methoxycarbonyl)benzylamino]heptanedihydrochloride

Example II-41

7-Acetylamino-4,4-diphenyl-1-(β-phenethylamino)heptane dihydrochloride

Example II-42

7-Acetylamino-1-[2-(6,7-dimethoxy-1,2,3,4-tetrahydronaphthylamino)]-4,4-diphenylheptanedihydrochloride

Example II-43

7-Acetylamino-1-{N-benzyl-N-[2-(6,7-dimethoxy-1,2,3,4-tetrahydronaphthyl)]amino}-4,4-diphenylheptanedihydrochloride

Example II-44

1'-(7-Acetylamino-4,4-diphenylheptyl)-3,4-dihydro-8-methoxyspiro[naphthalene-2(1H),2'-piperidine]dihydrochloride

Example II-45

1'-(7-Acetylamino-4,4-diphenylheptyl)-3,4-dihydro-6-methoxyspiro[naphthalene-2(1H),2'-piperidine]dihydrochloride

Example II-46

1'-(7-Acetylamino-4,4-diphenylheptyl)-3,4-dihydro-6,7-dimethoxyspiro[naphthalene-2(1H),2'-piperidine]dihydrochloride

Example II-47

1'-[7-(Cyclohexylacetyl)amino-4,4-diphenylheptyl]-3,4-dihydro-6,7-dimethoxyspiro[naphthalene-2(1H),2'-piperidine]hydrochloride

Example II-48

3,4-Dihydro-6,7-dimethoxy-1'-[4,4-diphenyl-7-(phenylacetylamino)heptyl]spiro[naphthalene-2(1H),2'-piperidine]hydrochloride

Example II-49

3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-[(2-fluorophenylacetyl)amino]heptyl}spiro[naphthalene-2(1H),2'-piperidine]hydrochloride

Example II-50

3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-[(4-fluorophenylacetyl)amino]heptyl}spiro[naphthalene-2(1H),2'-piperidine]hydrochloride

Example II-51

3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-[(4-chlorophenylacetyl)amino]heptyl}spiro[naphthalene-2(1H),2'-piperidine]hydrochloride

Example II-52

3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-[(3-nitrophenylacetyl)amino]heptyl}spiro[naphthalene-2(1H),2'-piperidine]hydrochloride

Example II-53

3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-[(4-nitrophenylacetyl)amino]heptyl}spiro[naphthalene-2(1H),2'-piperidine]hydrochloride

Example II-54

3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-[(4-methylphenylacetyl)amino]heptyl}spiro[naphthalene-2(1H),2'-piperidine]hydrochloride

Example II-55

3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-[(4-trifluoromethylphenylacetyl)amino]heptyl}spiro[naphthalene-2(1H),2-piperidine]hydrochloride

Example II-56

3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-[(2-methoxyphenylacetyl)amino]heptyl}spiro[naphthalene-2(1H),2'-piperidine]hydrochloride

Example II-57

3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-[(3-methoxyphenylacetyl)amino]heptyl}spiro[naphthalene-2(1H),2'-piperidine]hydrochloride

Example II-58

3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-[(4-methoxyphenylacetyl)amino]heptyl}spiro[naphthalene-2(1H),2'-piperidine]hydrochloride

Example II-59

3,4-Dihydro-6,7-dimethoxy-1'-{7-[(3,4-dimethoxyphenylacetyl)amino]-4,4-diphenylheptyl}spiro[naphthalene-2(1H),2'-piperidine]hydrochloride

Example II-60

3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-[(3,4-methylenedioxyphenylacetyl)amino]heptyl}spiro[naphthalene-2(1H),2'-piperidine]hydrochloride

Example II-61

3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-[(phenoxyacetyl)amino]heptyl}spiro[naphthalene-2(1H),2'-piperidine]hydrochloride

Example II-62

3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-[(2-thienylacetyl)amino]heptyl}spiro[naphthalene-2(1H),2'-piperidine]hydrochloride

Example II-63

3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-[(3-thienylacetyl)amino]heptyl}spiro[naphthalene-2(1H),2'-piperidine]hydrochloride

Example II-64

3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-[(3-phenylpropionyl)amino]heptyl}spiro[naphthalene-2(1H),2'-piperidine]hydrochloride

Example II-65

3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-{[3-(4-methoxyphenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine]hydrochloride

Example II-66

3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-[(1-naphthylacetyl)amino]heptyl}spiro[naphthalene-2(1H),2'-piperidine]hydrochloride

Example II-67

3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-[(2-naphthylacetyl)amino]heptyl}spiro[naphthalene-2(1H),2'-piperidine]hydrochloride

Example II-68

3,4-Dihydro-6,7-dimethoxy-1'-{4,4-bis(4-fluorophenyl)-7-[(4-methoxyphenylacetyl)amino]heptyl}spiro[naphthalene-2(1H),2'-piperidine]hydrochloride

Example II-11

1-(3-Aminobenzylamino)-4,4-diphenyl-5-(tosylamino)pentane

To a solution of4,4-diphenyl-1-(3-nitrobenzylamino)-5-(tosylamino)pentane (0.17 g) inethanol (10 ml) was added hydrochloric acid (0.1 ml) as well as 10%palladium-on-carbon (80 mg) and the mixture was subjected to catalytichydrogenation at atmospheric temperature and pressure. The catalyst wasthen removed from the reaction mixture and the filtrate was concentratedto dryness. The group was dissolved in water and the solution was madebasic with aqueous ammonia. The resulting precipitate was recovered byfiltration, rinsed with water, and dried to provide the title compound(0.12 g) as light-tan powder.

Example II-17 4,4-Diphenyl-5-mesylamino-1-(4-phenylpiperidino)pentaneHydrochloride

To a solution of 5-amino-4,4-diphenyl-1-(4-phenylpiperidino)pentane (0.4g) and triethylamine (0.42 ml) in methylene chloride (15 ml) was addedmethanesulfonyl chloride (0.1 ml) dropwise under ice-cooling andstirring. After completion of dropwise addition, the mixture wasreturned to room temperature and stirred for another 3 hours. Thisreaction mixture was washed with water, dried over anhydrous sodiumsulfate, and concentrated to dryness. The group was purified by silicagel column chromatography to provide the hydrochloride of the titlecompound (0.25 g) as colorless powder.

The compounds of Examples II-18 through II-24, II-30, II-32 throughII-33, II-37 through II-38 were respectively synthesized in the samemanner as Example II-17.

Example II-18

5-Benzenesulfonylamino-4,4-diphenyl-1-(4-phenylpiperidino)pentane

Example II-19

4,4-Diphenyl-1-(4-phenylpiperidino)-5-(2,4,6-trimethylbenzenesulfonylamino)pentane

Example II-20

4,4-Diphenyl-1-(4-phenylpiperidino)-5-(2,4,6-triisopropylbenzenesulfonylamino)pentane

Example II-21

4,4-Diphenyl-5-(1-naphthylsulfonylamino)-1-(4-phenylpiperidino)pentane

Example II-22

4,4-Diphenyl-5-(2-naphthylsulfonylamino)-1-(4-phenylpiperidino)pentane

Example II-23

3,4-Dihydro-6-methoxy-1'-(5-acetylamino-4,4-diphenylpentyl)spiro[naphthalene-2(1H),2'-piperidine]dihydrochloride

Example II-24

3,4-Dihydro-6-methoxy-1'-(5-tosylamino-4,4-diphenylpentyl)spiro[naphthalene-2(1H),2'-piperidine]dihydrochloride

Example II-30

4-(4-Methoxyphenyl)-5-(1-naphthylsulfonylamino)-4-phenyl-1-(4-phenylpiperidino)pentanehydrochloride

Example II-32

4,4-Bis(4-chlorophenyl)-1-[4-(4-fluorophenyl)piperazin-1-yl]-5-(mesylamino)pentanedihydrochloride

Example II-33

4,4-Bis(4-chlorophenyl)-1-[4-(4-fluorophenyl)piperazin-1-yl]-5-(tosylamino)pentanedihydrochloride

Example II-37

3,4-Dihydro-6-methoxy-1'-(6-acetylamino-4,4-diphenylhexyl)spiro[naphthalene-2(1H),2'-piperidine]dihydrochloride

Example II-38

3,4-Dihydro-6-methoxy-1'-(6-tosylamino-4,4-diphenylhexyl)spiro[naphthalene-2(1H),2'-piperidine]hydrochloride

Example II-39

3,4-Dihydro-6-methoxy-1'-(6-benzylamino-4,4-diphenylhexyl)spiro[naphthalene-2(1H),2'-piperidine]dihydrochloride

The structural formulas and physical properties of the above compoundsare shown below.

                                      TABLE 17                                    __________________________________________________________________________     ##STR118##                                                                   Ex-                                              Elemental Analysis           am-                          Melting             [Cald./(Found)]              ple                                                                              X Y R   R.sub.1       m n x                                                                             Point (°C.)                                                                  .sup.1 HNMR (δ.sub.ppm,                                                 CDCl.sub.3)   C   H  N                     __________________________________________________________________________    II-1                                                                             H H CHO N(CH.sub.3).sub.2                                                                           1 3 --                                                                            98-99 1.21-1.31(2H, m), 2.04-2.22 (2H, m),                                          2.09(6H, s), 4.05 (2H, d), 5.16(1H, br                                        s), 7.13-7.37(10H, m), 8.09 (1H,                                                             ##STR119##                  II-2                                                                             H H CHO                                                                                ##STR120##   1 3 1                                                                             97-105                                                                              1.20-1.36(2H, m), 2.04(3H, s),                                                2.02-2.15(2H, m), 2.28 (2H, t),                                               3.36(2H, s), 4.04 (2H, d), 5.11(1H, br                                        t), 7.10-7.37(15H, m), 8.06 (1H,                                                             ##STR121##                  II-3                                                                             H H CHO                                                                                ##STR122##   1 3 1     1.26(2H, m), 2.00-2.30(6H, m),                                                3.64(4H, t)4.04(2H, d), 5.00-5.20(1H,                                         br s), 7.10- 7.40(9H, m), 8.09(1H,                                                           ##STR123##                  II-4                                                                             H H CHO                                                                                ##STR124##   1 3 1                                                                             123-126                                                                             1.29(2H, m), 2.09(2H, m), 2.38(4H, t),                                        2.49(4H, m), 2.84(4H, m), 4.05(2H, d),                                        .10(1H, br s), 7.00-7.40 (14H, m),                                            8.09(1H, d)                                                                                  ##STR125##                  II-5                                                                             H H CHO                                                                                ##STR126##   1 3 1     1.20-1.40(2H, m), 1.55-2.23 (8H, m),                                          2.29(2H, t), 2.35- 2.50(1H, m),                                               2.90(2H, d), 4.06(2H, d),                                                     5.10-5.20(1H, br s), 7.10-7.35(15H,                                           m), 8.11(1H, d)                            __________________________________________________________________________

                                      TABLE 18                                    __________________________________________________________________________    Ex-                               Melting        Elemental Analysis           am-                               Point                                                                              .sup.1 HNMR (δ.sub.ppm,                                                           [Cald./(Found)]              ple                                                                              X Y R   R.sub.1            m n x                                                                             (°C.)                                                                       CDCl.sub.3)                                                                             C   H  N                     __________________________________________________________________________    II-6                                                                             H H CHO                                                                                ##STR127##        1 3 2                                                                             145-148                                                                            1.20-1.40(2H, m), 2.10-2.40(4H,                                               m), 2.45(4H, t), 3.05(4H, t),                                                 4.06(2H, d), 5.10 (1H, br s),                                                 6.80-7.00 (4H, m), 7.10-7.40 (10H,                                            m), 8.10(1H, d)                                                                          ##STR128##                  II-7                                                                             H H CHO                                                                                ##STR129##        1 3 2    1.05-1.30(2H, m), 1.35-2.80(18H,                                              m), 3.76(3H, s), 4.02(2H, d),                                                 5.30-5.40(1H, br t), 6.60-6.70                                                (2H, m), 6.96(1H,                                                             d), 7.10-7.35(10H, m), 8.08(1H,                                                          ##STR130##                  II-8                                                                             H H Ts                                                                                 ##STR131##        1 3 1    1.06-1.22(2H, m), 2.10-2.21(2H,                                               m), 2.40(3H, s), 2.50(2H, t),                                                 3.55, 3.66(2H each, t), 7.02-7.37                                             (17H, m), 7.59(2H, d)                                                                    ##STR132##                  II-9                                                                             H H Ts                                                                                 ##STR133##        1 3 1                                                                             115-118                                                                            1.07-1.22(2H, m), 2.04, 2.40(3H                                               each, s), 2.08-2.18(2H, m),                                                   2.24(2H, t), 3.34(2H, s), 3.56(2H,                                            d), 4.16 (1H, br t), 7.05, 1.06,                                              7.58(2H each, d), 7.13-7.37(13H,                                              m)                                                                                       ##STR134##                  II-10                                                                            H H Ts                                                                                 ##STR135##        1 3 1                                                                             111-115                                                                            1.09-1.25(2H, m), 2.15-2.25(2H,                                               m), 2.41(3H, s), 2.53(2H, t),                                                 3.55(2H, d), 3.78 (2H, s),                                                    3.95(1H, br t), 7.02-7.09(4H, m),                                             7.18-7.31(8H, m), 7.47(1H, t),                                                7.57-7.63(3H, m), 8.06-8.18(2H,                                               m),                                                                                      ##STR136##                  II-11                                                                            H H Ts                                                                                 ##STR137##        1 3 --   1.06-1.22(2H, m), 2.10-2.20(2H,                                               m), 2.40(3H, s), 2.50 (2H, t),                                                3.55, 3.59 (2H each, s), 3.66(1H,                                             br s), 6.52-6.55 (3H, m),                                                     7.00-7.10 (4H, m), 7.16-7.29 (8H,                                             m), 7.58(2H, d)                                                                          ##STR138##                  __________________________________________________________________________

                                      TABLE 19                                    __________________________________________________________________________    Ex-                                              Elemental Analysis           am-                           Melting            [Cald./(Found)]              ple                                                                              X Y R R.sub.1        m n x Point (°C.)                                                                  .sup.1 HNMR (δ.sub.ppm,                                                 CDCl.sub.3)  C   H  N                     __________________________________________________________________________    II-12                                                                            H H Ts                                                                               ##STR139##    1 3 1       1.05-1.24(2H, m), 2.11-2.20 (2H, m),                                          2.40(3H, s), 2.50 (2H, t), 3.54(2H,                                           d), 3.71 (2H, s), 3.91(3H, s), 3.98                                           (1H, br s), 7.01-7.08(4H, m),                                                 7.17-7.30(8H, m), 7.32- 7.51(2H, m),                                          7.59(2H, dd), 7.92(2H,                                                                      ##STR140##                  II-13                                                                            H H Ts                                                                               ##STR141##    1 3 2 176-181                                                                             1.09-1.27(2H, m), 2.11- 2.22(2H, m),                                          2.41(3H, s), 2.54(2H, t), 3.55,                                               3.80(2H each, s), 7.01-7.30(14H, m),                                          7.55-7.68(3H, m), 8.53 (1H,                                                                 ##STR142##                  II-14                                                                            H H Ts                                                                               ##STR143##    1 3 1       1.03-1.20(2H, m), 1.55(8H, s),                                                2.06-2.17(2H, m), 2.33 (2H, t),                                               2.42(3H, s), 2.47 (4H, br s),                                                 3.56(2H, s), 7.03-7.11(4H, m), 7.16-                                          7.30(8H, m), 7.58(2H,                                                                       ##STR144##                  II-15                                                                            H H Ts                                                                               ##STR145##    1 3 --                                                                              146-147                                                                             1.11-1.30(2H, m), 2.12- 2.26(2H, m),                                          2.28(2H, t), 2.42(3H, s), 2.43(4H,                                            t), 3.13(4H, t), 3.56(2H, d),                                                 3.94(1H, t), 6.80-6.95(3H, m), 7.06,                                          7.07, 7.59(2H each, d),                                                       7.18-7.31(10H, m)                                                                           ##STR146##                  II-16                                                                            H H Ts                                                                               ##STR147##    1 3 1 112-117                                                                             1.15-1.30(2H, m), 2.12-2.25 (2H, m),                                          2.29(2H, t), 2.42 (3H, s), 2.49,                                              3.03(4H each, t), 3.57(2H, d),                                                3.85(3H, s), 3.99(1H, br t),                                                  6.82-7.31 (16H, m), 7.59(2H,                                                                ##STR148##                  II-17                                                                            H H Ms                                                                               ##STR149##    1 3 1 123-126                                                                             1.18-1.39(2H, m), 1.62-2.58 (14H, m),                                         2.86-3.05(2H, d), 3.75-3.90(2H, d),                                           4.60-4.77  (1H, br s), 7.13-7.37(15H,                                         m)                                                                                          ##STR150##                  __________________________________________________________________________

    TABLE 20      -  Elemental Analysis      Melting [Cald./(Found)]      Example X Y R R.sub.1 m n x Point (°C.) .sup.1      HNMR (δ.sub.ppm, CDCl.sub.3) C  H       N      II-18 H H      ##STR151##      ##STR152##      1 3 -- 145-147 1.12-1.31(2H, m), 1.50-2.55(11H, m),2.78-2.94(2H, d),     3.53-3.65(2H, d), 4.01-4.16(1H, br s), 7.01-7.12(4H, m), 7.13-7.37(11H,     m), 7.40-7.62(3H, m), 7.66-7.75(2H, m)      ##STR153##     II-19 H H      ##STR154##      ##STR155##      1 3 -- 107-108 1.03-1.23(2H, m), 1.53-2.33(14H, m),2.35-2.45(6H, s),     2.73-2.91(2H, d), 3.44-3.55(2H, d), 4.03-4.19(1H, m), 6.87-6.92(2H,     s),7.01-7.10(4H, dd), 7.13-7.34(11H, m)      ##STR156##     II-20 H H      ##STR157##      ##STR158##      1 3 -- 139-140 1.10-1.33(20H, m), 1.53-2.53(11H, m),2.75-2.97(3H, m),     3.55-3.68(2H, d), 3.80-4.17(3H, m), 7.05-7.36(17H, m)      ##STR159##     II-21 H H      ##STR160##      ##STR161##      1 3 --  0.85-1.08(2H, m), 1.43-2.05(10H, m),2.32-2.53(1H, m), 2.66-2.82(     2H, m), 3.47-3.63(2H, d), 4.28-4.46(1H, br s), 6.88-7.34(15H, m),     7.49-7.65(3H, m), 7.89-7.97(1H,m), 8.02-8.11(1H, d), 8.20-8.35(2H, m)     II-22 H H      ##STR162##      ##STR163##      1 3 -- 150-152 1.05-1.27(2H, m), 1.50-1.90(6H, m),2.05-2.25(4H, m),     2.28-2.55(1H, m),2.70-2.85(2H, d), 3.58-3.68(2H, d), 4.13-4.30(1H, m),     7.00-7.34(15H, m), 7.56-7.71(3H, m), 7.86-7.99(3H, m), 8.31-8.35(1H, d)      ##STR164##     II-23 H H Ac      ##STR165##      1 3 2  1.40-3.10(24H, m), 3.77(3H, s), 4.00(2H,br s), 6.20-6.30(1H,     br), 6.60-6.75(2H,m), 7.01(1H, d), 7.12-7.32(10H, m)      ##STR166##

    TABLE 21      -  Elemental Analysis      Melting [Cald./(Found)]      Example X Y R R.sub.1 m n x Point (°C.) .sup.1      HNMR (δ.sub.ppm, CDCl.sub.3) C  H       N      II-24 H H Ts      ##STR167##      1 3 2  1.00-1.17(2H, m), 1.35-2.80(21H, m), 3.55(2H, d), 3.77(3H, s),     4.00-4.15(1H, br t), 6.60-6.75(2H, m), 6.90-7.30(13H, m), 7.57(2H, d)      ##STR168##     II-25 4-Cl H CHO      ##STR169##      1 3 1 118-123 1.20-1.39(2H, m), 1.40-2.19(8H, m), 2.29(2H, t), 2.32-2.53     (1H, m), 2.89(2H, d), 4.03(2H, dd), 5.21(1H, br t),7.06-7.37(14H, s),     8.09(1H, d)      ##STR170##     II-26 4-Cl H CHO      ##STR171##      1 3 2 133-138 1.20-1.36(2H, m), 2.03-2.15(2H, m), 2.31(2H, t), 2.46,3.14     (4H each, t), 4.03(2H, d), 5.10(1H, br t), 6.80-6.93(3H, m), 7.06-7.38(11     H, m), 8.10(1H, d)      ##STR172##     II-27 4-Cl H CHO      ##STR173##      1 3 2 138-143 1.17-1.39(2H, m), 2.09, 2.30(2H each, t), 2.46, 3.06(4Heac     h, t), 4.03(2H, d), 5.11(1H, br t), 6.80-7.00(4H, m),7.07-7.38(9H, m),     8.09(1H, d)      ##STR174##     II-28 4-Cl H CHO      ##STR175##      1 3 --  1.10-1.30(2H, m), 1.97-2.10(2H, m), 2.24(2H, t), 2.22-2.42(8H,     m), 3.99(2H, d), 4.18(1H, s), 5.17(1H, br t),7.03-7.42(19H, m), 8.07(1H,     d)      ##STR176##     II-29 4-MeO H CHO      ##STR177##      1 3 1  1.15-1.40(2H, m), 1.60-2.20(8H, m), 2.28(2H, t), 2.30-2.50(1H,     m), 2.90(2H, d), 3.79(3H, s), 4.02(2H, d),5.10-5.30(1H, m), 6.83(2H, d),     7.00-7.20(12H, m),8.09(2H, s)      ##STR178##

    TABLE 22      -  Elemental Analysis      Melting [Cald./(Found)]      Example X Y R R.sub.1 m n x Point (°C.) .sup.1      HNMR (δ.sub.ppm, CDCl.sub.3) C  H       N      II-30 4-MeO H      ##STR179##      ##STR180##      1 3 1 115-120 1.05-1.30(2H, m), 1.70-2.60(11H, m), 3.01(2H, d),     3.52(2H, dd), 3.72(3H, s), 4.50-4.70(1H, br), 6.61(2H, d), 6.85(2H, d),     6.90-6.98(2H, m), 7.05-7.30(8H, m), 7.48-7.60(3H, m),7.88-7.93(1H, m),     8.04(1H, d), 8.21(1H, dd)8.25-8.32(1H, m)      ##STR181##      II-31 4-Cl 4-Cl CHO      ##STR182##      1 3 2  1.20-1.38(2H, m), 2.00-2.10(2H, m), 2.40-2.50(4H, m), 3.06(4H,     t), 4.00(2H, d), 5.00-5.15(1H, br), 6.80-7.15(8H, m), 7.22-7.357.35(4H,     m), 8.10(1H, d)      ##STR183##      II-32 4-Cl 4-Cl Ms      ##STR184##      1 3 2  1.15-1.35(2H, m), 2.15-2.25(2H, m), 2.40(2H,t), 2.51-2.61(4H,     m), 2.70(3H, s), 3.11(4H,t), 3.76(2H, d), 4.25(1H, br t), 6.80-7.30(12H,     m)      ##STR185##      II-33 4-Cl 4-Cl Ts      ##STR186##      1 3 2 166-168 1.10-1.30(2H, m), 2.07-2.17(2H, m), 2.29(2H, t), 2.43(3H,     s), 2.41-2.51, (4H, m),3.08(4H, t), 3.52(2H, d), 4.17(1H, br t),5.80-7.00     (8H, m), 7.20-7.30(6H, m), 7.56(2H, d)      ##STR187##      II-34 H H CHO      ##STR188##      1 4 2 135-140 1.01-1.20(2H, m), 1.36-1.58(2H, m), 2.05-2.36(2H, m),     2.29(2H, t), 2.52, 3.08(4Heach, t), 4.04(2H, d), 5.12(1H, br t),     6.81-7.01(4H, m), 7.12-7.39(10H, m), 8.09(1H, d)      ##STR189##

    TABLE 23      -  Elemental Analysis      Melting [Cald./(Found)]      Example X Y R R.sub.1 m n x Point (°C.) .sup.1      HNMR (δ.sub.ppm, CDCl.sub.3) C  H       N      II-35 H H CHO      ##STR190##      2 3 2 148-152 1.17-1.35(2H, m), 2.10-2.22(2H, m), 2.32,2.35(2H each,     t), 2.44, 3.05(4H each, t),3.03-3.13(2H, m), 5.20(1H, br s), 6.79-6.98(4H     , m), 7.12-7.32(10H, m), 7.98(1H, d)      ##STR191##     II-36 H H Ts      ##STR192##      2 3 1  1.08-1.27(2H, m), 1.60-2.10(8H, m), 2.20-2.39(4H, m), 2.41(3H,     s), 2.38-2.52(1H, m),2.65-2.69(2H, m), 2.86(2H, d), 4.29(1H,br s),     7.05-7.35(17H, m), 7.58(2H, d)      ##STR193##     II-37 H H Ac      ##STR194##      2 3 2  1.27-1.79(7H, m), 1.82(3H, s), 1.82-1.96(2H,m), 2.00-2.20(3H,     m), 2.33(2H, t), 2.48-2.62(2H, m), 2.65-3.09(8H, m), 3.77(3H, s),     5.75(1H, br s), 6.63, 6.96(1H each, d), 6.70(1H,dd), 7.11-7.32(10H, m)      ##STR195##     II-38 H H Ts      ##STR196##      2 3 1  0.96-1.15(2H, m), 1.35-2.08(11H, m), 2.18-2.80(11H, m), 2.41,     3.77(3H each, s), 4.10(1H, br s), 6.61-6.72(2H, m), 6.95(1H, d),7.02-7.30     (12H, m), 7.57(2H, d)      ##STR197##     II-39 H H      ##STR198##      ##STR199##      2 3 2  1.50-2.36(13H, m), 2.50-3.10(11H, m), 3.77(3H, s), 3.87(2H, s),     6.64(1H, d), 6.73(1H,dd), 7.00(1H, d), 7.11-7.38(13H, m), 7.44-7.52(2H,     m)      ##STR200##

                                      TABLE 24                                    __________________________________________________________________________                                                     Elemental Analysis                                                            [Cald./(Found)]              Example                                                                            X Y R R.sub.1          m n x .sup.1 HNMR (δ.sub.ppm,                                                 CDCl.sub.3)    C   H  N                     __________________________________________________________________________    II-40                                                                              H H Ac                                                                               ##STR201##      3 3 2 1.10-1.35(4H, m), 1.90, 3.91(3H each,                                         s), 2.02-2.17(4H, m), 2.59 (2H, t),                                           3.14(2H, q), 3.79(2H, s), 5.69(1H, br                                         t), 7.10-7.30 (10H, m), 7.40(1H, t),                                          7.50-7.59 (1H, m), 7.95(1H,                                                                   ##STR202##                  II-41                                                                              H H Ac                                                                               ##STR203##      3 3 2 1.13-1.46(4H, m), 1.94(3H,                                                    s), 2.02-2.20(4H, m), 2.73(2H, t),                                            2.97(4H, s), 3.15(2H, q), 6.04 (1H, br                                        t), 7.08-7.33(15H, m)                                                                         ##STR204##                  II-42                                                                              H H Ac                                                                               ##STR205##      3 3 2 1.10-1.30(2H, m), 1.45-1.70(2H, m),                                           1.97(3H, s), 2.05-2.35(5H,                                                    m), 2.70-3.20(9H, m), 3.77(3H, s),                                            3.82(3H, s), 6.50(2H, d), 6.70-                                               6.80(1H, br), 7.05-7.30(10H,                                                                  ##STR206##                  II-43                                                                              H H Ac                                                                               ##STR207##      3 3 2 1.00-1.20(4H, m), 1.50-2.15(11H, m),                                          2.46(2H, t), 2.60-2.90(5H, m), 3.10(2H,                                       dd), 3.57(2H, dd), 3.82 (3H, s),                                              3.84(3H, s), 5.00-5.10(1H, br),                                               6.55(2H, d), 7.08-7.35(15H,                                                                   ##STR208##                  II-44                                                                              H H Ac                                                                               ##STR209##      3 3 2 1.10-1.30(2H, m), 1.35-1.80(4H, m),                                           1.91(3H, s), 2.00-2.18(2H,                                                    m), 2.20-2.40(1H, m), 2.40-2.60 (4H,                                          m), 2.70-2.95(3H, m), 3.16(2H, dd),                                           3.81(3H, s), 5.48- 5.64(1H, br),                                              6.68(2H, t), 7.02- 7.30(11H,                                                                  ##STR210##                  __________________________________________________________________________

    TABLE 25      - Elemental Analysis      [Cald./(Found)]      Example X Y R R.sub.1 m n x .sup.1 HNMR (δ.sub.ppm, CDCl.sub.3) C      H       N      II-45 H H Ac      ##STR211##      3 3 2 1.00-2.80(24H, m), 3.15(2H, dd), 3.77(3H, s),5.20-5.40(1H, br),     6.60-6.70(2H, m), 6.95(1H,d), 7.10-7.30(10H, m)      ##STR212##     II-46 H H Ac      ##STR213##      3 3 2 1.10-1.30(4H, m), 1.42-2.87(23H, m), 3.17(2H, q), 3.83, 3.85(3H     each, s), 5.40(1H,br), 6.56, 6.58(1H each, s), 7.10-7.30(10H,m)      ##STR214##     II-47 H H      ##STR215##      ##STR216##      3 3 1 0.80-2.17(29H, m), 2.20-2.82(8H, m), 3.18(2H, q), 3.83, 3.85(3H     each, s), 5.23(1H,br t), 6.55, 6.58(1H each, s), 7.10-7.30(10H, m)      ##STR217##     II-48 H H      ##STR218##      ##STR219##      3 3 1 1.02-1.22(4H, m), 1.40-2.80(20H, 3), 3.14(2H,q), 3.56(2H, s),     3.83(6H, s), 6.52, 6.56(1Heach, s), 7.00-7.38(15H, m)      ##STR220##     II-49 H H      ##STR221##      " 3 3 1 0.98-1.22(4H, m), 1.38-2.11(12H, m), 2.17-2.80(8H, m), 3.15(2H,     q), 3.53(2H, s), 3.83,3.84(3H each, s), 5.34(1H, br t), 6.54, 6.57(1H,     each, s), 7.00-7.32(14H, m)      ##STR222##     II-50 H H      ##STR223##      " 3 3 1 1.00-1.21(4H, m), 1.38-2.10(12H, m), 2.17-2.80(8H, m), 3.14(2H,     q), 3.47(2H, s), 3.823.84(3H each, s), 5.24(1H, br t), 6.55, 6.57(1H     each, s), 6.95-7.29(14H, m)      ##STR224##

    TABLE 26      - Elemental Analysis      [Cald./(Found)]      Example X Y R R.sub.1 m n x .sup.1 HNMR (δ.sub.ppm, CDCl.sub.3) C      H       N      II-51 H H      ##STR225##      ##STR226##      3 3 1 1.00-1.20(4H, m), 1.35-2.80(20H, m), 3.15(2H, q), 3.47(2H, s),     3.83, 3.84(3H each),s), 5.20-5.35(1H, br), 6.55, 6.58(1H each,s),     7.05-7.32(14H, m)      ##STR227##     II-52 H H      ##STR228##      " 3 3 1 1.00-1.25(4H, m), 1.35-2.80(20H, m), 3.16(2H, q), 3.56(2H, s),     3.82, 3.84(3H each,s), 5.50-5.65(1H, br), 6.55, 6.58(1H each,s),     7.05-7.30(12H, m), 7.40-7.70(2H, m),      ##STR229##     II-53 H H      ##STR230##      " 3 3 1 1.05-1.25(4H, m), 1.35-3.05(20H, m), 3.15(2H, q), 3.58(2H, s),     3.82, 3.84(3H each,s), 5.35-5.70(1H, br), 6.55, 6.57(1H each,s),     7.05-7.50(14H, m)      ##STR231##     II-54 H H      ##STR232##      " 3 3 1 1.05-1.30(4H, m), 1.41-1.68(6H, m), 1.80-2.00(6H, m), 2.32(3H,     s), 2.40-3.00(8H, m),3.10-3.20(2H, m), 3.51(2H, s), 3.83(6H, s),5.70-5.90     (1H, br), 6.55, 6.57(1H each, s),7.05-7.26(14H, m)      ##STR233##     II-55 H H      ##STR234##      " 3 3 1 1.05-1.20(4H, m), 1.32-1.58(6H, m), 1.60-2.08(6H, m), 2.24-2.96(     8H, m), 3.10-3.22(2H, m), 3.55(2H, s), 3.83, 3.84(3H each,s), 5.55-5.75(1     H, br), 6.55, 6.58(1H each,s), 7.07-7.27(10H, m), 7.39(2H, d), 7.58(2H,     d)      ##STR235##

    TABLE 27      - Elemental Analysis      [Cald./(Found)]      Example X Y R R.sub.1 m n x .sup.1 HNMR (δ.sub.ppm, CDCl.sub.3) C      H       N      II-56 H H      ##STR236##      ##STR237##      3 3 1 0.98-1.18(4H, m), 1.40-2.10(12H, m), 2.192.79(8H, m), 3.12(2H,     q), 3.52(2H, s), 3.78,3.83, 3.85(3H each, s), 5.53(19, br, t), 6.55,6.57(     1H each, s), 6.85-6.98(2H, m), 7.05-7.31(12H, m)      ##STR238##      II-57 H H      ##STR239##      " 3 3 1 0.98-1.20(4H, m), 1.40-2.08(12H, m), 2.20-2.79(8H, m), 3.13(2H,     q), 3.49(2H, s), 3.76,3.83, 3.84(3H each, s), 5.26(1H, br t), 6.54,6.57(1     H each, s), 6.76-6.85(3H, m), 7.05-7.29(11H, m)      ##STR240##      II-58 H H      ##STR241##      " 3 3 1 1.00-1.19(4H, m), 1.38-2.10(12H, m), 2.18-2.80(8H, m), 3.13(2H,     q), 3.46(2H, s), 3.77,3.83, 3.85(3H each, s), 5.23(1H, br t), 6.55,6.58(1     H each, s), 6.86(2H, d), 7.06-7.26(12H,m)      ##STR242##      II-59 H H      ##STR243##      " 3 3 1 0.98-1.18(4H, m), 1.33-2.10(12H, m), 2.20-2.80(8H, m), 3.15(2H,     q), 3.46(2H, s), 3.82,3.83, 3.84, 3.85(3H each, s), 5.24(1H, br t),6.55,     6.57(1H each, s), 6.70-6.82(3H, m), 7.03-7.28(10H, m)      ##STR244##

    TABLE 28      - Elemental Analysis      [Cald./(Found)]      Example X Y R R.sub.1 m n x .sup.1 HNMR (δ.sub.ppm, CDCl.sub.3) C      H       N      II-60 H H      ##STR245##      ##STR246##      3 3 1 0.98-1.20(4H, m), 1.35-2.80(20H, m), 3.14(2H, q), 3.42(2H, s),     3.83, 3.84(3H each,s), 5.27-5.30(1H, br), 5.91(2H, s), 6.55,6.57(1H     each, s), 6.62-6.80(3H, m), 7.05-7.29(10H, m)      ##STR247##      II-61 H H      ##STR248##      " 3 3 1 1.00-2.80(24H, m), 3.27(2H, q), 3.83, 3.84(3H each, s),     4.45(2H, s), 6.41(1H, br t),6.55, 6.57(1H each, s), 6.87-7.95(15H, m)      ##STR249##      II-62 H H      ##STR250##      " 3 3 1 1.00-1.20(4H, m), 1.30-2.80(20H, m), 3.16q), 3.72(2H, s), 3.82,     3.84(3H each, s),5.50-5.70(1H, br), 6.55, 6.58(1H each, s),6.85-7.00(2H,     m), 7.05-7.30(11H, m)      ##STR251##      II-63 H H      ##STR252##      " 3 3 1 1.00-1.20(4H, m), 1.33-2.10(13H, m), 2.20-2.80(7H, m), 3.15(2H,     q), 3.55(2H, m), 3.833.84(3H each, s), 5.31(1H, br t), 6.55, 6.57(1H     each, s), 6.97(1H, d), 7.05-7.37      ##STR253##      II-64 H H      ##STR254##      " 3 3 1 1.06-1.70(8H, m), 1.84-2.17(4H, m), 2.41-3.00(16H, m), 3.17(2H,     q), 3.83(6H, s), 6.55, 6.56(1H each, s), 7.08-7.30(15H, m)      ##STR255##

    TABLE 29      - Elemental Analysis      [Cald./(Found)]      Example X Y R R.sub.1 m n x .sup.1 HNMR (δ.sub.ppm, CDCl.sub.3) C      H       N      II-65 H H      ##STR256##      ##STR257##      3 3 1 1.02-1.21(4H, m), 1.38-2.10(12H, m), 2.35,2.86(2H each, t),     2.25-2.85(8H, m), 3.13(2H, q), 3.73, 3.82, 3.84(3H each, s), 5.22(1H, br     t), 6.55, 6.57(1H each, s), 6.79(2H, d), 7.05-7.30(12H, m)      ##STR258##      II-66 H H      ##STR259##      " 3 3 1 0.86-1.06(4H, m), 1.38-2.01(12H, m),2.13-2.79(8H, m), 3.07,(2H,     q), 3.83, 3.74(3H each, s), 3.99(2H, s), 5.14(1H, br t),6.55, 6.57(1H     each, s), 6.94(4H, dd),7.06-7.22(6H, m), 7.34-7.56(4H, m),7.80-8.00(3H,     m)      ##STR260##      II-67 H H      ##STR261##      " 3 3 1 0.96-1.20(4H, m), 1.33-2.07(12H, m),2.13-2.80(8H, m), 3.14(2H,     q), 3.69(2H,s), 3.83, 3.84(3H each, s), 5.27(1H, br t),6.54, 6.57(1H     each, s), 7.00-7.25(10H,m), 7.35(1H, dd), 7.43-7.52(2H, m), 7.69(1H, s),     7.75-7.87(3H, m)      ##STR262##      II-68 4-F 4-F      ##STR263##      " 3 3 1 0.95-1.18(4H, m), 1.38-2.05(12H, m),2.70-2.79(8H, m), 3.13(2H,     q), 3.47(2H,s), 3.78, 3.83, 3.84(3H each, s), 5.25(1H,br t), 6.55,     6.57(1H each, s), 6.83-7.18(12H, m)      ##STR264##

Example III-1 (1) 4,4-Diphenyl-5-hydroxyl-6-heptenenitrile

Under argon gas, 4,4-diphenyl-4-formylbutanenitrile (5.0 g) wasdissolved in dry tetrahydrofuran (200 ml). Then, 1M vinylmagnesiumbromide-tetrahydrofuran (30 ml) was added dropwise -40° C. Aftercompletion of addition, the reaction temperature was allowed to risegradually to 0° C. (over 3 hours). After completion of the reaction, asaturated aqueous solution of ammonium chloride was added to thereaction mixture and the insoluble matter was filtered off. The filtratewas extracted with ethyl acetate, washed, dried, and concentrated andthe group was purified by silica gel column chromatography. The activefraction was concentrated to provide the title compound as oil (5.4 g).

¹ H-NMR (CDCl₃, δ): 1.90-2.28(2H,m), 2.41-2.70(2H,m), 4.90(1H,dd),5.21(2H,dd), 5.49-5.66(1H,m), 7.20-7.36(10H,m)

(2)7-(6,7-Dimethoxy-1,2,3,4-tetrahydronaphthalene-2-spiro-2'-piperidin-1'-yl)-4,4-diphenyl-5-heptenenitrileHydrochloride

In tetrahydrofuran (5 ml) was dissolved4,4-diphenyl-5-hydroxyl-6-heptenenitrile (377 mg) followed by additionof phosphorus tribromide (0.04 ml) with cooling on an ice-water bath.The mixture was stirred at room temperature for 1 hour, at the end ofwhich time it was extracted with ethyl acetate. The allyl bromide thusobtained was not purified but used in crude form in the next reaction.

In N,N-dimethylformamide (3 ml) was suspended6,7-dimethoxy-1,2,3,4-tetrahydronaphthalene-2-spiro-2'-piperidinehydrochloride (193 mg) followed by addition of potassium carbonate (90mg) and the mixture was stirred for 30 minutes. Then, a solution of thecrude allyl bromide in N,N-dimethylformamide was added to the abovemixture and a further amount (90 mg) of potassium carbonate was added.The reaction was carried out at 60° C. for 15 hours and this reactionmixture was extracted with ethyl acetate, washed, dried, andconcentrated. The group was purified by silica gel column chromatographyand the active fraction was concentrated and treated with 4N HCl-ethylacetate to provide the hydrochloride (200 mg, powder).

¹ H-NMR (CDCl₃, δ): 1.50(6H,br), 1.65-1.95(2H,m), 2.04-2.14(2H,m),2.57-2.88(8H,m), 3.07-3.31(2H,m), 3.83(6H,s), 5.32(1H,dt), 6.15(1H,d),6.54(1H,s), 6.57(1H,s), 7.10-7.34(10H,m)

(3)1-(7-Amino-4,4-diphenyl-2-heptenyl)-6',7'-dimethoxy-1',2',3',4'-tetrahydronaphthalene-2'-spiro-2-piperidine

7-(6,7-Dimethoxy-1,2,3,4-tetrahydronaphthalene-2-spiro-2'-piperidin-1'-yl)-4,4-diphenyl-5-heptenenitrile(free base, 200 mg) was mixed with hydrazine hydrate (4 ml) and Raneynickel (0.6 g) in the presence of ethanol (10 ml) and the reaction wascarried out at 80° C. for 2 hours. After the reaction, the nickel wasfiltered off and the filtrate was concentrated to provide the titlecompound (free base, 170 mg).

¹ H-NMR (CDCl₃, δ): 1.46-1.98(14H,m), 2.20-2.30(2H,m), 2.56-2.74(6H,m),3.07-3.30(2H,m), 3.83(6H,s), 5.28 (1H,dt), 6.19(1H,d), 6.55(1H,s),6.57(1H,s), 7.15-7.30(10H,m)

Example III-2N-(7-(6,7-Dimethoxy-1,2,3,4-tetrahydronaphthalene-2-spiro-2'-piperidin-1'-yl)-4,4-diphenyl-5-heptenyl)-3-(4-methoxyphenyl)propionamideHydrochloride

In ethyl acetate (5 ml) was dissolved1-(7-amino-4,4-diphenyl-2-heptenyl)-6',7'-dimethoxy-1',2',3',4'-tetrahydronaphthalene-2'-spiro-2-piperidine(free base, 150 mg) followed by addition of a saturated aqueous solutionof sodium carbonate (3 ml). With this biphasic solution being stirred,3-(4-methoxyphenyl)propionyl chloride (170 mg)-ethyl acetate solution (1ml) was gradually added. After completion of the reaction, the organiclayer was washed with water and concentrated and the group was purifiedby silica gel column chromatography. The active fraction wasconcentrated and treated with 4N HCl-ethyl acetate to provide thehydrochloride (60 mg, powder).

¹ H-NMR (CDCl₃, δ): 1.16-1.32(2H,m), 1.45-1.66(6H,m), 1.72-2.04(2H,m),2.16-2.30(2H,m), 2.41 (2H,m), 2.68(4H,m), 2.89(4H,m), 3.19(4H,m), 3.70(3H,s), 3.82(6H,s), 5.2-5.4(1H,m), 6.15(1H,d), 6.5 5(1H,s), 6.57(1H,s),6.76(2H,d), 7.09-7.31 (12H,m)

The following compounds were obtained according to the same method ofExample III-2.

Example IV-14,4-Diphenyl-1-[(6-methoxy-1,2,3,4-tetrahydro-2-naphthyl)amino]-7-{[3-(4-methoxyphenyl)propionyl]amino}heptaneHydrochloride ##STR265##

¹ H-NMR (CDCl₃, δ): 1.04-1.25(4H,m), 1.40-1.53(1H,m), 1.80-2.19(6H,m),2.29-2.56(3H,m), 2.62(2H,t), 2.70-2.95(6H,m), 3.13(2H,q), 3.72,3.75(3Heach,s), 5.30(1H,br t), 6.58-6.73(2H,m), 6.78(2H,d), 6.95(1H,d),7.02-7.30(12H,m).

Example IV-24,4-Diphenyl-1-[3-(4-methoxyphenyl)piperidino]-7-{[3-(4-methoxyphenyl)propionyl]amino}heptaneHydrochloride ##STR266##

¹ H-NMR (CDCl₃, δ): 1.00-1.45(4H,m), 1.55-2.15(10H,m), 2.19-2.37(4H,m),2.63-2.90(5H,m), 3.13(2H,q), 3.73,3.78(3H each,s), 5.13(1H,br t),6.75-6.86(4H,m), 7.03-7.30(14H,m).

Example IV-34,4-Diphenyl-1-(4-phenylpiperidino)-7-[(3-phenylpropionyl)amino]heptaneHydrochloride ##STR267##

¹ H-NMR (CDCl₃, δ): 1.00-1.38(4H,m), 1.59-1.90(4H,m), 1.95-2.30(4H,m),2.34-2.60(6H,m), 2.86-3.20(7H,m), 5.73(1H,br t), 7.08-7.35(20H,m).

Example IV-44,4-Diphenyl-1-[4-(3-methoxyphenyl)piperidino]-7-[(3-phenylpropionyl)amino]heptaneHydrochloride ##STR268##

¹ H-NMR (CDCl₃, δ): 1.00-1.35(4H,m), 1.70-2.13(8H,m), 2.28-2.61(6H,m),2.87-3.05(5H,m), 3.13(2H,q), 3.77(3H,s), 5.51(1H,br t), 6.69-6.80(3H,m),7.08-7.30(16H,m).

Example IV-54,4-Diphenyl-1-[4-(4-methoxyphenyl)piperidino]-7-{[3(4-methoxyphenyl)propionyl]amino}heptaneHydrochloride ##STR269##

¹ H-NMR (CDCl₃, δ): 1.04-1.28(4H,m), 1.54-2.17(10H,m), 2.19-2.45(5H,m),2.86(4H,t), 3.14(2H,q), 3.72,3.76(3H each,s), 5.22(1H,br t),6.73-6.86(4H,m), 7.02-7.30(14H,m).

Example IV-64,4-Diphenyl-7-{[3-(4-methoxyphenyl)propionyl]-amino}-1-[2,3,4,5-tetrahydro-3(1H)-benzazepin-3-yl]heptaneHydrochloride ##STR270##

¹ H-NMR (CDCl₃, δ): 1.03-1.29(4H,m), 1.98-2.15(4H,m), 2.28-2.53(8H,m),2.80-2.92(6H,m), 3.13(2H,q), 3.72(3H,s), 5.23(1H,br t), 6.78(2H,d),7.00-7.32(16H,m).

Example IV-7 1-[7-Acetyl-2,3,4,5-tetrahydro-3(1H)-benzazepin-3-yl]-4,4-diphenyl-7-{[3-(4-methoxyphenyl)propionyl]-amino}heptaneHydrochloride ##STR271##

¹ H-NMR (CDCl₃, δ): 1.04-1.25(4H,m), 2.00-2.55(12H,m), 2.56(3H,s),2.80-2.94(6H,m), 3.15(2H,q), 3.73(3H,s), 5.21(1H,br t), 6.78(2H,d),7.04-7.31(13H,m), 7.62-7.72(2H,m).

Example IV-84,4-Diphenyl-1-(7,8-dimethoxy-2,3,4,5-tetrahydro-3(1H)-benzazepin-3-yl)-7-{[3-(4-methoxyphenyl)propionyl]amino}heptaneHydrochloride ##STR272##

¹ H-NMR (CDCl₃, δ): 1.06-1.30(4H,m), 2.01-2.12(4H,m), 2.35,2.87(2Heach,t), 2.33-2.52(6H,m), 2.74-2.85(4H,m), 3.15(2H,q), 3.74(3H,s),3.83(6H,s), 5.17(1H,br t), 6.60(2H,s), 6.79,7.09(2H each,d),7.10-7.31(10H,m).

Example IV-91-(8,9-Dimethoxy-6,6-dimethyl-1,2,3,4,5,6-hexahydro-3-benzazocin-3-yl)-4,4-diphenyl-7-{[3-(4-methoxyphenyl)propionyl]amino}heptaneHydrochloride ##STR273##

¹ H-NMR (CDCl₃, δ): 0.78-0.98(4H,m), 1.38(6H,s), 1.50-1.72(4H,m),1.79-2.22(6H,m), 2.30-2.62(6H,m), 2.87(2H,t), 3.07(2H,q),3.73,3.77,3.79(3H each,s), 5.54(1H,br t), 6.47(1H,s), 6.78(2H,d),6.90-6.99(4H,m), 7.04-7.27(9H,m).

Example IV-104,4-Diphenyl-7-{[3-(4-methoxyphenyl)propionyl]amino}-1-(cis-1,2,3,4,4a,9,10,10a-octahydrobenzo[f]quinolin-1-yl)heptaneHydrochloride ##STR274##

¹ H-NMR (CDCl₃, δ): 1.00-1.30(4H,m), 1.50-3.20(24H,m), 3.73(3H,s),5.15(1H,br s), 6.78(2H,d), 6.98-7.30(16H,m).

Example IV-111-(3-Aza-6-methyl-1,1a,2,3,4,4a-hexahydro-9-fluorenon-3-yl)-4,4-diphenyl-7-{[3-(4-methoxyphenyl)propionyl]amino}heptaneHydrochloride ##STR275##

¹ H-NMR (CDCl₃, δ): 1.00-1.30(4H,m), 1.45-3.40(21H,m), 3.73(3H,s),5.20(1H,br t), 6.76(2H,d), 7.06-7.30(14H,m), 7.64(1H,d).

Example IV-123,4-Dihydro-1'-{4,4-diphenyl-7-{[3-(4-methoxyphenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),2'-pyrrolidine]Hydrochloride ##STR276##

¹ H-NMR (CDCl₃, δ): 1.00-1.30(4H,m), 1.40-2.25(8H,m), 2.26-2.90(12H,m),3.13(2H,q), 3.73(3H,s), 5.12(1H,br t), 6.79(2H,d), 7.00-7.30(16H,m).

Example IV-133,4-Dihydro-6-methoxy-1'-{4,4-diphenyl-7-{[3-(4-methoxyphenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine]Dihydrochloride ##STR277##

¹ H-NMR (CDCl₃, δ): 0.98-1.23(4H,m), 1.30-2.20(14H,m), 2.22-2.78(8H,m),2.86(2H,t), 3.13(2H,q), 3.73,376(3H each,s), 5.10-5.28(1H,br),6.60-6.73(2H,m), 6.78(2H,d), 6.94(1H,d), 7.02-7.29(14H,m).

Example IV-146-Ethoxy-3,4-dihydro-1'-{4,4-diphenyl-7-{[3-(4-methoxyphenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine]Hydrochloride ##STR278##

¹ H-NMR (CDCl₃, δ): 1.02-1.23(5H,m), 1.33-1.54(9H,m), 1.95-2.11(5H,m),2.28-2.43(4H,m), 2.43-2.56(2H,m), 2.65-2.80(4H,m), 2.80-2.92(2H,m),3.07-3.20(2H,m), 3.74(3H,s), 3.99(2H,q), 5.24(1H,br), 6.63(1H,s),6.66(1H,d), 6.79(2H,d), 6.94(1H,d), 7.06-7.30(12H,m).

Example IV-153,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-{[3-(4-dimethylaminophenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine]Hydrochloride ##STR279##

¹ H-NMR (CDCl₃, δ): 0.95-1.20(4H,m), 1.32-2.16(14H,m), 2.19-2.95(12H,m),3.12(2H,q), 3.44(2H,s), 3.83,3.84(3H each,s), 5.20-5.34(1H,br),6.55,6.57(1H each,s), 6.58(1H,d), 7.02-7.26(12H,m).

Example IV-163,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-{[3-(4-fluorophenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine]Hydrochloride ##STR280##

¹ H-NMR (CDCl₃, δ): 1.00-1.20(4H,m), 1.30-2.10(12H,m), 2.15-3.00(12H,m),3.13(2H,q), 3.82,3.84(3H each,s), 5.12-5.24(1H,br), 6.55,6.57(1Heach,s), 6.88-7.30(14H,m)

Example IV-173,4-Dihydro-6,7-dimethoxy-1'-{7-{[3-(4-chlorophenyl)propionyl]amino}-4,4-diphenylheptyl}spiro[naphthalene-2(1H),2'-piperidine]Hydrochloride ##STR281##

¹ H-NMR (CDCl₃, δ): 1.00-1.22(4H,m), 1.35-2.15(12H,m), 2.16-2.81(10H,m),2.89(2H,t), 3.13(2H,q), 3.82,3.84(3H each,s), 5.23(1H,br t),6.55,6.58(1H each,s), 7.00-7.30(14H,m).

Example IV-183,4Dihydro-6,7-dimethoxy-1'-{7-{[3-(3,5-difluorophenyl)propionyl]amino}-4,4-diphenylheptyl}spiro[naphthalene-2(1H),2'-piperidine]Hydrochloride ##STR282##

¹ H-NMR (CDCl₃, δ): 0.97-1.22(4H,m), 1.33-2.15(12H,m), 2.20-2.80(10H,m),2.91(2H,t), 3.12(2H,q), 3.82,3.84(3H each,s), 5.15-5.30(1H,br),6.55,6.57(1H each,s), 6.66-6.80(2H,m), 7.09-7.30(11H,m).

Example IV-193,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-{[3-(4-pyridyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine]Dihydrochloride ##STR283##

¹ H-NMR (CDCl₃, δ): 1.00-1.25(4H,m), 1.33-1.73(6H,m), 1.73-2.18(6H,m),2.20-2.81(8H,m), 2.39,2.93(2H each,t), 3.15(2H,q), 3.83,3.84(3H each,s),5.28(1H,br t), 6.55,6.58(1H each,s), 7.08-7.30(12H,m), 8.46(2H,dd).

Example IV-203,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-{[2-(5-methoxyindan)carbonyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine]Hydrochloride ##STR284##

¹ H-NMR (CDCl₃, δ): 1.02-1.30(4H,m), 1.40-2.80(20H,m), 3.02-3.17(5H,m),3.20(2H,q), 3.76,3.82,3.84(3H each,s), 5.33(1H,br t), 6.54,6.57(1Heach,s), 6.70(1H,dd), 6.74(1H,d), 7.07(1H,d), 7.10-7.30(10H,m).

Example IV-213,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-{[3-(3,4-methylenedioxyphenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine]Hydrochloride ##STR285##

¹ H-NMR (CDCl₃, δ): 1.00-1.20(4H,m), 1.35-2.89(24H,m), 3.14(2H,q),3.82,3.84(3H each,s), 5.28(1H,br t), 5.87(2H,s), 6.54-6.70(5H,m),7.00-7.30(10H,m).

Example IV-223,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-{[3-(4-methoxyphenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine]-1-oneHydrochloride ##STR286##

¹ H-NMR (CDCl₃, δ): 1.01-1.26(2H,m), 1.40-1.60(2H,m), 1.60-1.73(4H,brs), 1.80-2.45(14H,m), 2.76-3.02(4H,m), 3.05-3.21(2H,m),3.73,3.89,3.91(3H each,s), 5.38(1H,br t), 6.61(1H,s), 6.78(1H,d),7.00-7.26(12H,m), 7.49(1H,s).

Example IV-233,4-Dihydro-6-methoxy-5-nitro-1'-{4,4-diphenyl-7-{[3-(4-methoxyphenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine]Hydrochloride ##STR287##

¹ H-NMR (CDCl₃, δ): 1.02-1.32(5H,m), 1.39-1.61(4H,m), 1.73-1.93(2H,m),1.33-2.20(5H,m), 2.28-2.50(6H,m), 2.50-2.77(4H,m), 2.78-2.99(2H,m),3.03-3.24(2H,m), 3.73,3.84(3H each,s), 5.39(1H,br), 6.72-6.88(3H,m),7.02-7.33(13H,m).

Example IV-243,4-Dihydro-6-methoxy-7-nitro-1'-{4,4-diphenyl-7-{[3-(4-methoxyphenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine]Hydrochloride ##STR288##

¹ H-NMR (CDCl₃, δ): 1.01-1.20(5H,m), 1.32-1.73(6H,m), 1.82-2.18(5H,m),2.22-2.51(6H,m), 2.52-2.76(2H,m), 2.76-2.94(4H,m), 3.06-3.20(2H,m),3.74,3,90(3H each,s), 5.16(1H,br), 6.78(1H,s), 6.79(2H,d),7.04-7.31(12H,m), 7.61(1H,s).

Example IV-257-Amino-3,4-dihydro-6-methoxy-1'-{4,4-diphenyl-7-{[3-(4-methoxyphenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine]Dihydrochloride ##STR289##

¹ H-NMR (CDCl₃, δ): 0.80-1.20(5H,m), 1.37-1.87(6H,m), 1.92-2.11(5H,m),2.22-2.56(6H,m), 2.58-2.76(4H,m), 2.78-2.92(2H,m), 3.04-3.12(2H,m),3.72,3.78(3H each,s), 5.34(1H,br), 6.40,6.49(1H each,s), 6.78(2H,d),7.03-7.28(12H,m),

Example IV-267-Acetylamino-3,4-dihydro-6-methoxy-1'-{4,4-diphenyl-7-{[3-(4-methoxyphenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine]Hydrochloride ##STR290##

¹ H-NMR (CDCl₃, δ): 1.00-1.23(5H,m), 1.38-1.90(6H,m), 1.91-2.12(5H,m),2.22(3H,s), 2.24-2.52(6H,m), 2.60-2.76(4H,m), 2.76-2.92(2H,m),3.07-3.20(2H,m), 3.73,3.83(3H each,s), 5.55(1H,br), 6.58(1H,s),6.78(2H,d), 7.04-7.28(12H,m), 7.69(1H,s), 8.06(1H,s).

Example IV-277-Acetyl-3,4-dihydro-6-methoxy-1'-{4,4-diphenyl-7-{[3-(4-methoxyphenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine]Hydrochloride ##STR291##

¹ H-NMR (CDCl₃, δ): 1.01-1.24(5H,m), 1.35-1.90(6H,m), 1.91-2.19(5H,m),2.24-2.53(6H,m), 2.58(3H,s), 2.62-2.96(6H,m), 3.05-3.20(2H,m),3.72,3.86(3H each,s), 5.67(1H,br), 6.68(1H,s), 6.78(2H,d),7.05-7.27(12H,m), 7.47(1H,s).

Example IV-283,4-Dihydro-6,7-methylenedioxy-1'-{4,4-diphenyl-7-{[3-(4-methoxyphenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine]Hydrochloride ##STR292##

¹ H-NMR (CDCl₃, δ): 1.02-1.30(5H,m), 1.38-1.88(6H,m), 1.89-2.20(5H,m),2.28-2.45(4H,m), 2.46-2.56(2H,m), 2.56-2.75(4H,m), 2.75-2.98(2H,m),3.03-3.23(2H,m), 3.73(3H,s), 5.58(1H,br), 5.86(2H,s), 6.51(1H,s),6.55(1H,s), 6.79(2H,d), 7.02-7.32(12H,m).

Example IV-296,7-Diethoxy-3,4-dihydro-1'-{4,4-diphenyl-7-{[3-(4-methoxyphenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine]Hydrochloride ##STR293##

¹ H-NMR (CDCl₃, δ): 1.00-1.30(5H,m), 1.30-1.60(10H,m), 1.60-1.90(2H,m),1.90-2.19(5H,m), 2.26-2.44(4H,m), 2.44-2.58(2H,m), 2.58-2.78(4H,m),2.78-2.93(2H,m), 3.03-3.20(2H,m), 3.72(3H,s), 3.90-4.12(4H,m),5.55(1H,br), 6.56,6.58(1H each,s), 6.78(2H,d), 7.03-7.30(12H,m).

Example IV-303,4-Dihydro-1'-{4,4-diphenyl-7-{[3-(4-methoxyphenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),2'-hexamethyleneimine]Hydrochloride ##STR294##

¹ H-NMR (CDCl₃, δ): 0.85-2.20(20H,m), 2.20-2.91(10H,m), 3.14(2H,q),3.72(3H,s), 5.07(1H,br t), 6.78(2H,d), 7.00-7.30(16H,m).

Example IV-31(+)-3,4-Dihydro-6-methoxy-1'-{4,4-diphenyl-7-{[(4-methoxyphenyl)acetyl]amino}heptyl}spiro-[naphthalene-2(1H),2'-piperidine]Hydrochloride ##STR295##

¹ H-NMR (CDCl₃, δ): 0.98-1.22(4H,m), 1.30-2.20(14H,m), 2.20-2.78(8H,m),2.86(2H,t), 3.13(2H,q), 3.72,3.76(3H each,s), 5.12-5.30(1H,br),6.59-6.73(2H,m), 6.78(2H,d), 6.94(1H,d), 7.02-7.29(14H,m).

[α]_(D) =+3.4° (c 0.893 in MeOH)

Example IV-32(-)-3,4-Dihydro-6-methoxy-1'-{4,4-diphenyl-7-{[(4-methoxyphenyl)acetyl]amino}heptyl}spiro-[naphthalene-2(1H),2'-piperidine]Hydrochloride ##STR296##

¹ H-NMR (CDCl₃, δ): 0.98-1.22(4H,m), 1.30-2.20(14H,m), 2.20-2.78(8H,m),2.86(2H,t), 3.13(2H,q), 3.72,3.76(3H each,s), 5.12-5.30(1H,br),6.59-6.73(2H,m), 6.78(2H,d), 6.94(1H,d), 7.02-7.29(14H,m).

[α]_(D) =-2.8° (c 0.828 in MeOH)

Example IV-33(-)3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-{[(4-methoxyphenyl)acetyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine]-1-oneHydrochloride ##STR297##

¹ H-NMR (CDCl₃, δ): 1.00-1.25(4H,m), 1.35-2.52(18H,m), 2.75-2.95(4H,m),3.15(2H,q), 3.73,3.89,3.92(3H each,s), 5.38(1H,br t), 6.61(1H,s),6.78(2H,d), 7.05-7.27(12H,m), 7.50(1H,s).

[α]_(D) =-9.7° (c 0.624 in MeOH)

Example IV-34(-)-3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-{[(4-fluorophenyl)acetyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine]Hydrochloride ##STR298##

¹ H-NMR (CDCl₃, δ): 1.02-1.30(5H,m), 1.36-1.61(4H,m), 1.61-1.90(2H,m),1.90-2.18(8H,m), 2.23-2.47(2H,m), 2.47-2.60(2H,m), 2.60-2.80(4H,m),3.06-3.22(2H,m), 3.47(2H,s), 3.82,3.83(3H each,s), 5.68(1H,br),6.55,6.58(1H each,s), 6.94-7.30(14H,m).

[α]_(D) =-3.4° (C 0.327 in MeOH)

Example IV-35(+)-3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-{[(4-fluorophenyl)acetyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine]Hydrochloride ##STR299##

¹ H-NMR (CDCl₃, δ): 1.02-1.30(5H,m), 1.36-1.61(4H,m), 1.61-1.90 (2H,m),1.90-2.18(5H,m), 2.23-2.47(2H,m), 2.47-2.60 (2H,m), 2.60-2.80(4H,m),3.06-3.22(2H,m), 3.47(2H,s), 3.82,3.83(3H each,s), 5.68(1H,br),6.55,6.58(1H each,s), 6.94-7.30(14H,m).

[α]_(D) =+3.8° (c 0.330 in MeOH)

Example IV-36(-)-3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-{[3-(4-fluorophenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine]Hydrochloride ##STR300##

¹ H-NMR (CDCl₃, δ): 1.02-1.30(5H,m), 1.37-1.90(6H,m), 1.91-2.18(5H,m),2.28-2.46(4H,m), 2.48-2.59(2H,m), 2.59-2.80(4H,m), 2.80-2.97(2H,m),3.04-3.20(2H,m), 3.82,3.83(3H each,s), 5.53(1H,br), 6.55,6.57(1Heach,s), 6.92(2H,t), 7.07-7.31(12H,m).

Example IV-37(+)-3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-{[3-(4-fluorophenyl)propionyl]amino}heptyl]spiro[naphthalene-2(1H),2'-piperidine]Hydrochloride ##STR301##

¹ H-NMR (CDCl₃, δ): 1.02-1.30(5H,m), 1.37-1.90(6H,m), 1.91-2.18(5H,m),2.28-2.46(4H,m), 2.48-2.59(2H,m), 2.59-2.80(4H,m), 2.80-2.97(2H,m),3.04-3.20(2H,m), 3.82,3.83(3H each,s), 5.53(1H,br), 6.55,6.57(1Heach,s), 6.92(2H,t), 7.07-7.31(12H,m).

[α]_(D) =+1.98° (c 0.514 in MeOH)

Example IV-38(+)-3,4-Dihydro-6,7-dimethoxy-1'-{7-{[3-(4-chlorophenyl)propionyl]amino}-4,4-diphenylheptyl}spiro[naphthalene-2(1H),2'-piperidine]Hydrochloride ##STR302##

¹ H-NMR (CDCl₃, δ): 1.03-1.34(5H,m), 1.40-1.90(6H,m), 1.91-2.20(5H,m),2.32-2.48(4H,m), 2.50-2.62(2H,m), 2.62-2.82(4H,m), 2.82-2.97(2H,m),3.04-3.20(2H,m), 3.82(6H,s), 5.74(1H,br), 6.54,6.56(1H each,s),7.04-7.30(14H,m).

[α]_(D) =+0.20° (c 0.04 in MeOH)

Example IV-39(-)-3,4-Dihydro-6,7-dimethoxy-1'-{7-{[3-(4-chlorophenyl)propionyl]amino}-4,4-diphenylheptyl}spiro[naphthalene-2(1H),2'-piperidine]Hydrochloride ##STR303##

¹ H-NMR (CDCl₃, δ): 1.03-1.34(5H,m), 1.40-1.90(6H,m), 1.91-2.20(5H,m),2.32-2.48(4H,m), 2.50-2.62(2H,m), 2.62-2.82(4H,m), 2.82-2.97(2H,m),3.04-3.20(2H,m), 3.82(6H,s), 5.74(1H,br), 6.54,6.56(1H each,s),7.04-7.30(14H,m).

Example IV-40(-)-3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-{[3-(4-methoxyphenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine]Hydrochloride ##STR304##

¹ H-NMR (CDCl₃, δ): 1.00-1.22(4H,m), 1.32-2.15(12H,m), 2.17-2.92(12H,m),3.14(2H,q), 3.73,3.83,3.84(3H each,s), 5.19(1H,br s), 6.56,6.58(1Heach,s), 6.79(2H,d), 7.04-7.30(12H,m).

[α]_(D) =-3.31° (C 0.651 in MeOH)

Example IV-41(+)-3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-{[3-(4-methoxyphenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine]Hydrochloride ##STR305##

¹ H-NMR (CDCl₃, δ): 1.00-1.22(4H,m), 1.32-2.15(12H,m), 2.17-2.92(12H,m),3.14(2H,q), 3.73,3.83,3.84(3H each,s), 5.19(1H,br s), 6.56,6.58(1Heach,s), 6.79(2H,d), 7.04-7.30(12H,m).

[α]_(D) =+3.50° (C 0.712 in MeOH)

Example IV-423,4-Dihydro-4'-{4,4-diphenyl-7-{[3-(4-methoxyphenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),3'-morpholine]Hydrochloride ##STR306##

¹ H-NMR (CDCl₃, δ): 1.00-1.30(4H,m), 1.58-2.50(12H,m), 2.58-3.00(6H,m),3.13(2H,q), 3.45-3.80(7H,m), 5.08-5.20(1H,br), 6.78(2H,d),7.00-7.33(16H,m).

Example IV-433,4-Dihydro-7-methoxy-4'-{4,4-diphenyl-7-{[3-(4-methoxyphenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),3'-morpholine]Hydrochloride ##STR307##

¹ H-NMR (CDCl₃, δ): 1.00-1.30(4H,m), 1.60-1.80(2H,m), 1.97-2.50(10H,m),2.60-2.92(6H,m), 3.13(2H,q), 3.48-3.70(4H,m), 3.73,3.77(3H,each,s),5.08-5.20(1H,br t), 6.60-6.73(1H,m), 6.78(2H,d), 6.94-7.30(14H,m).

Example IV-443,4-Dihydro-6,7-dimethoxy-4'-{4,4-diphenyl-7-{[3-(4-methoxyphenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),3'-morpholine]Hydrochloride ##STR308##

¹ H-NMR (CDCl₃, δ): 1.00-1.28(4H,m), 1.58-1.90(2H,m), 1.92-2.55(10H,m),2.60-2.80(4H,m), 2.86(2H,t), 3.13(2H,q), 3.48-3.70(4H,m), 3.73(3H,s),3.83(6H,s), 5.08-5.20(1H,br), 6.57,6.59(1H each,s), 6.78(2H,d),7.05-7.30(12H,m).

Example IV-453,4-Dihydro-6,7-dimethoxy-4'-methyl-1'-{4,4-diphenyl-7-{[3-(4-methoxyphenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperazine]Dihydrochloride ##STR309##

¹ H-NMR (CDCl₃, δ): 1.00-1.25(4H,m), 1.60-2.80(23H,m), 2.87(2H,m),3.15(2H,q), 3.73(3H,s), 3.84(6H,s), 5.00-5.25(1H,br), 6.50-6.65(2H,m),6.79(2H,d), 7.05-7.33(12H,m).

    ______________________________________                                        Formulation Example 1                                                         ______________________________________                                        (1) Compound of Example II-45                                                                      10.0       g                                             (2) Lactose          60.0       g                                             (3) Corn starch      35.0       g                                             (4) Gelatin          3.0        g                                             (5) Magnesium stearate                                                                             2.0        g                                             ______________________________________                                    

Using 30 ml of an aqueous solution of gelatin (10 wt. % concentration,3.0 g as gelatin), a mixture of 10.0 g of the compound obtained inExample II-45, 60.0 g of lactose, and 35.0 g of corn starch wasgranulated by means of a 1 mm-mesh sieve, dried at 40° C., andre-sieved. The granules thus prepared were mixed with 2.0 g of magnesiumstearate and the mixture was compressed. The core tablets thus obtainedwere coated using an aqueous suspension containing sucrose, titaniumdioxide, talc and gum arabic. The coated tablets were then glazed withbeeswax to provide 1000 finished tablets.

    ______________________________________                                        Formulation Example 2                                                         ______________________________________                                        (1) Compound of Example II-45                                                                      10.0       g                                             (2) Lactose          70.0       g                                             (3) Corn starch      50.0       g                                             (4) Soluble starch   7.0        g                                             (5) Magnesium stearate                                                                             3.0        g                                             ______________________________________                                    

Using 70 ml of aqueous starch solution (7.0 g as soluble starch), amixture of 10.0 g of the compound obtained in Example II-45 and 3.0 g ofmagnesium stearate was granulated, dried, and mixed with 70.0 g oflactose and 50.0 g of corn starch. The whole mixture was then compressedto provide 1000 tablets.

Test Example (A) Preparation of ¹²⁵ I-leuprolerin

A tube was filled with 10 μl of an aqueous solution of leuprolerin(3×10⁴ M) and lactoperoxidase (0.01 mg/ml) followed by addition of 10 μlof Na¹²⁵ I solution (37 MBq). After stirring, 10 μl of 0.001% H₂ O₂ wasadded and the reaction was conducted at room temperature for 20 minutes.The reaction was stopped by adding 700 μl of 0.05% TFA and the reactionmixture was subjected to reversed-phase HPLC under the conditions setforth below. ¹²⁵ I-leuprolerin was eluted with a retention time of 26-27minutes.

Column: TSK Gel ODS-80™ CTR (4.6 mm×10 cm)

Eluent: Solvent A (0.05% TFA) and solvent B (40% CH₃ CN-0.05% TFA)

Gradient: 0 min (100% solvent A)-3 min (100% solvent A)-7 min (50%solvent A+50% solvent B)-40 min (100% solvent B)

Elution temperature: room temperature

Flow rate: 1 ml/min.

(B) Preparation of a Rat GnRH Receptor-containing Anterior PituitaryMembrane Fraction

Forty rats (8 weeks old, male) of Wistar strain were decapitated underno anesthesia and the anterior pituitary isolated from each animal waswashed with an ice-cooled homogenate buffer (25 mM Tris(tris(hydroxylmethyl)aminomethane)-HCl, 0.3M sucrose, 1 mM EGTA(ethylene-bis(oxyethylenenitrilo)tetraacetic acid), 0.25 mM PMSF(phenylmethylsulfonyl fluoride), 10 U/ml aprotinin, 1 μg/ml pepstatin,20 μg/ml leupeptin, 100 μg/ml phosphoramidon, 0.03% sodium azide; pH7.5). The anterior pituitary was suspended in 2 ml of the samehomogenate buffer as above and homogenized using a Polytron homogenizer.The homogenate thus prepared was centrifuged at 700 xg for 15 minutesand the supernatant was transferred to an ultracentrifuge cuvette andfurther centrifuged at 100,000 xg for 1 hour to provide a membranefraction pellet. This pellet was suspended in 2 ml of an assay buffer(25 mM Tris-HCl, 1 mM ethylenediaminetetraacetic acid (EDTA), 0.1%bovine serum albumin (BSA), 0.25 mM PMSF, 1 μg/ml pepstatin, 20 μg/mlleupeptin, 100 μg/ml phosphoramidon, 0.03% sodium azide; pH 7.5) andcentrifuged at 100,000 xg for 1 hour. The membrane fraction recovered asa pellet was resuspended in 10 ml of the same assay buffer as above,distributed into vials, preserved at -80° C., and reconstituted beforeuse.

(C) Preparation of a Bovine GnRH Receptor-containing Anterior PituitaryMembrane Fraction

A bovine GnRH receptor-containing anterior pituitary membrane fractionwas prepared in the same manner as (B) except that the supernatant fromthe 10,000 xg centrifugate was centrifuged at 100,000 xg for 1 hour toprovide a membrane fraction pellet.

(D) Preparation of a Human GnRH Receptor-containing CHO (Chinese HamsterOvarian) Cell Membrane Fraction

Human GnRH receptor-expressed CHO cells (10⁹ cells) were suspended inphosphate buffered saline supplemented with EDTA (PBS-EDTA) andcentrifuged at 100 xg for 5 minutes. To the sediment was added 10 ml ofa cell homogenate buffer (10 mM NaHCO₃, 5 mM EDTA, pH 7.5) and themixture was homogenized using a Polytron homogenizer. The homogenate wascentrifuged at 400 xg for 15 minutes and the supernatant was transferredto an ultracentrifuge cuvette and centrifuged at 100,000 xg for 1 hourto prepare a membrane fraction pellet. This pellet was suspended in 2 mlof the assay buffer and further centrifuged at 100,000 xg for 1 hour.The membrane fraction recovered as a pellet was resuspended in 20 ml ofthe assay buffer, distributed into vials, preserved at -80° C., andreconstituted before use.

(E) Determination of the ¹²⁵ I-leuprolerin Binding Inhibition Rate

The rat and human membrane fractions prepared under (B) and (D) wererespectively diluted with the assay buffer to make 200 μg/ml each and188 μl aliquots of each dilution were distributed into tubes. The bovinemembrane fraction prepared under (C) was diluted with the assay bufferto make 750 μg/ml and 188 μl aliquots of the dilution were distributedinto tubes. When the rat anterior pituitary membrane fraction was used,2 μl of 0.1 mM compound/60% dimethyl sulfoxide (DMSO) and 10 μl of 38 nM¹²⁵ I-leuprolerin were concurrently added. When the bovine anteriorpituitary membrane fraction and the human GnRH receptor-expressed CHOcell membrane fraction were used, 2 μl of 2 mM compound/60% DMSO and 10μl of 38 nM ¹²⁵ I-leuprolerin were concurrently added. For determinationof maximum binding, a reaction mixture was prepared by adding 2 μl of60% DMSO and 10 μl of 38 nM ¹²⁵ I-leuprolerin. For determination ofnon-specific binding, a reaction mixture was prepared using 2 μl of 100μM leuprolerin/60% DMSO and 10 μl of 3.8 nM ¹²⁵ I-leuprolerin.

When the rat and bovine anterior pituitary membrane fractions were used,each reaction was carried out at 4° C. for 90 minutes. On the otherhand, when the human GnRH receptor-expressed CHO cell membrane fractionwas used, the reaction was conducted at 25° C. for 60 minutes. Aftercompletion of the reaction, the reaction mixture was suction-filteredthrough a polyethyleneimine-treated Whatman glass filter (GF-F)[trademark;whatman]. After filtration, the radioactivity of the residual¹²⁵ I-leuprolerin on the filter was measured using a γ-counter.

The computation formula of (TB-SB)/(TB-NSB)×100 (SB=radioactivity boundin the presence of the test compound, TB=maximum amount of radioactivitybound, NSB=amount of radioactivity nonspecifically bound) was calculatedto find the binding inhibition rate for the test compound. Moreover, theinhibition rate was determined by varying the concentration of each testcompound and the concentration of the compound causing 50% inhibition ofbinding (IC₅₀ value) was calculated by Hill plot.

The results are shown in Table 30.

                  TABLE 30                                                        ______________________________________                                        GnRH-receptor binding inhibition assay                                                     GnRH-receptor binding                                            Compound     inhibitory activity (IC.sub.50, μM)                           of Example   Man        Rat                                                   ______________________________________                                        II-37                   0.3                                                     43                    0.2                                                     44                    0.4                                                     45                    0.08                                                    46                    0.003                                                   48         0.2        0.002                                                   50         0.08       0.0007                                                  51         0.08       0.002                                                   53         0.8        0.01                                                    58         0.11       0.0016                                                  59         0.4        0.02                                                    60         0.1        0.002                                                   61                    0.01                                                    63         0.4        0.001                                                   64         0.2        0.009                                                   65         0.02       0.001                                                   66         0.3        0.003                                                   68         0.4        0.009                                                 ______________________________________                                    

It is apparent from the results that compound (I), inclusive of itssalt, of this invention has excellent GnRH-receptor binding inhibitoryactivity.

Compound (I) of this invention, inclusive of its salt, inhibitssecretion of gonadotropic hormone in mammalian animals by way of itsGnRH-receptor antagonizing activity to control blood steroid hormonelevels so that it can be used in the prevention and treatment of variousdiseases, particularly in man.

While the present invention has been described with respect to what ispresently considered to be the preferred embodiments, it is to beunderstood that the invention is not limited to the disclosedembodiments. The present invention is intended to cover variousmodifications and equivalent arrangements included within the spirit andscope of the appended claims.

What is claimed is:
 1. A compound of the formula: ##STR310## wherein Ar¹and Ar² independently represent an optionally substituted aromaticgroup;P and Q independently represent a divalent aliphatic hydrocarbongroup having at least 2 carbon atoms, which may have either oxygen orsulfur within the carbon chain; R¹ and R³ independently represent i) anacyl group of --CO--R or --CONH--R wherein R represents an optionallysubstituted hydrocarbon group or an optionally substituted heterocyclicgroup, or ii) an optionally substituted hydrocarbon group; R² and R⁴independently represent hydrogen or an optionally substituted alkylgroup; R¹ and R² or R³ and R⁴, taken together with the adjacent nitrogenatom, may form an optionally substituted nitrogen-containingheterocyclic group; and j represents 0 or 1, or a salt thereof.
 2. Thecompound of claim 1 whereinAr¹ and Ar² are independently C₆₋₁₄ arylgroup which may be substituted by 1 to 5 substituents selected from thegroup consisting of halogen, C₁₋₃ alkylenedioxy, nitro, cyano,optionally halogenated C₁₋₆ alkyl, optionally halogenated C₃₋₆cycloalkyl, optionally halogenated C₁₋₆ alkoxy, optionally halogenatedC₁₋₆ alkylthio, hydroxyl, amino, mono-C₁₋₆ alkylamino, di-C₁₋₆alkylamino, C₁₋₆ alkyl-carbonylamino, C₁₋₆ alkyl-carbonyl, carboxyl,C₁₋₆ alkoxy-carbonyl, carbamoyl, mono-C₁₋₆ alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, sulfo, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₀aryl and C₆₋₁₀ aryloxy; P and Q are independently divalent C₂₋₆aliphatic hydrocarbon group which may have either oxygen or sulfurwithin the carbon chain; R¹ and R³ are independently i) an acyl group of--CO--R^(a) or --CONH--R^(a) wherein R^(a) is a) a C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₄ aryl or C₇₋₁₆ aralkylgroup which may be substituted by 1 to 5 substituents selected from thegroup consisting of halogen, C₁₋₃ alkylenedioxy, nitro, cyano,optionally halogenated C₁₋₆ alkyl, optionally halogenated C₃₋₆cycloalkyl, optionally halogenated C₁₋₆ alkoxy, optionally halogenatedC₁₋₆ alkylthio, hydroxyl, amino, mono-C₁₋₆ alkylamino, di-C₁₋₆alkylamino, C₁₋₆ alkyl-carbonylamino, C₁₋₆ alkyl-carbonyl, carboxyl,C₁₋₆ alkoxy-carbonyl, carbamoyl, mono-C₁₋₆ alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, sulfo, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₀aryl, C₆₋₁₀ aryloxy and 5- or 6-membered heterocyclic group, or b) a 5-to 10-membered heterocyclic group containing, besides carbon atom, 1 to4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom,which may be substituted by 1 to 5 substituents selected from the groupconsisting of halogen, C₁₋₃ alkylenedioxy, nitro, cyano, optionallyhalogenated C₁₋₆ alkyl, optionally halogenated C₃₋₆ cycloalkyl,optionally halogenated C₁₋₆ alkoxy, optionally halogenated C₁₋₆alkylthio, hydroxyl, amino, mono-C₁₋₆ alkylamino, di-C₁₋₆ alkylamino,C₁₋₆ alkyl-carbonylamino, C₁₋₆ alkyl-carbonyl, carboxyl, C₁₋₆alkoxy-carbonyl, carbamoyl, mono-C₁₋₆ alkylcarbamoyl, di-C₁₋ 6alkylcarbamoyl, sulfo, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₀aryl and C₆₋₁₀ aryloxy, or ii) a C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₆ cycloalkyl, C₆₋₁₄ aryl or C₇₋₁₆ aralkyl group which may besubstituted by 1 to 5 substituents selected from the group consisting ofhalogen, C₁₋ 3 alkylenedioxy, nitro, cyano, optionally halogenated C₁₋₆alkyl, optionally halogenated C₃₋₆ cycloalkyl, optionally halogenatedC₁₋₆ alkoxy, optionally halogenated C₁₋₆ alkylthio, hydroxyl, amino,mono-C₁₋₆ alkylamino, di-C₁₋₆ alkylamino, C₁₋₆ alkyl-carbonylamino, C₁₋₆alkyl-carbonyl, carboxyl, C₁₋₆ alkoxy-carbonyl, carbamoyl, mono-C₁₋₆alkylcarbamoyl, di-C₁₋₆ alkylcarbamoyl, sulfo, C₁₋₆ alkylsulfonyl, C₁₋₆alkylsulfinyl and 5- or 6-membered heterocyclic group; and R² and R⁴ areindependently hydrogen or a C₁₋₆ alkyl group which may be substituted by1 to 5 substituents selected from the group consisting of halogen,nitro, cyano, optionally halogenated C₃₋₆ cycloalkyl, optionallyhalogenated C₁₋₆ alkoxy, optionally halogenated C₁₋₆ alkylthio,hydroxyl, amino, mono-C₁₋₆ alkylamino, di-C₁₋₆ alkylamino, C₁₋₆alkyl-carbonylamino, C₁₋₆ alkyl-carbonyl, carboxyl, C₁₋₆alkoxy-carbonyl, carbamoyl, mono-C₁₋₆ alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, sulfo, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₀aryl and C₆₋₁₀ aryloxy, or R¹ and R² or R³ and R⁴, taken together withthe adjacent nitrogen atom, form a nitrogen-containing heterocyclicgroup of the formula: ##STR311## wherein ring A is a 4- to 8-memberedring which may be substituted by hydroxyl or oxo group; and Vis >O, >C═O, ##STR312## or >N--W in which W is a) hydrogen, b) a C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₄ aryl or C₇₋₁₆aralkyl group which may be substituted by 1 to 5 substituents selectedfrom the group consisting of halogen, C₁₋₃ alkylenedioxy, nitro, cyano,optionally halogenated C₁₋₆ alkyl, optionally halogenated C₃₋₆cycloalkyl, optionally halogenated C₁₋₆ alkoxy, optionally halogenatedC₁₋₆ alkylthio, hydroxyl, amino, mono-C₁₋₆ alkylamino, di-C₁₋₆alkylamino, C₁₋₆ alkyl-carbonylamino, C₁₋₆ alkyl-carbonyl, carboxyl,C₁₋₆ alkoxy-carbonyl, carbamoyl, mono-C₁₋₆ alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, sulfo, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl and 5- or6-membered heterocyclic group, or c) a 5- to 10-membered heterocyclicgroup, containing, besides carbon atom, 1 to 4 hetero atoms selectedfrom nitrogen atom, oxygen atom and sulfur atom, which may besubstituted by 1 to 5 substituents selected from the group consisting ofhalogen, C₁₋₃ alkylenedioxy, nitro, cyano, optionally halogenated C₁₋₆alkyl, optionally halogenated C₃₋₆ cycloalkyl, optionally halogenatedC₁₋₆ alkoxy, optionally halogenated C₁₋₆ alkylthio, hydroxyl, amino,mono-C₁₋₆ alkylamino, di-C₁₋₆ alkylamino, C₁₋₆ alkyl-carbonylamino, C₁₋6 alkyl-carbonyl, carboxyl, C₁₋₆ alkoxy-carbonyl, carbamoyl, mono-C₁₋₆alkylcarbamoyl, di-C₁₋₆ alkylcarbamoyl, sulfo, C₁₋₆ alkylsulfonyl, C₁₋₆alkylsulfinyl, C₆₋₁₀ aryl and C₆₋₁₀ aryloxy, and W^(a) is hydrogen orhydroxyl, ##STR313## wherein ring B is a 4- to 12-membered mono- orbicyclic ring optionally having an oxo group and optionally substitutedby 1 to 5 C₁₋₆ alkyl groups; and ring D is a 4- to 12-membered aromaticring which may be substituted by 1 to 5 substituents selected from thegroup consisting of halogen, C₁₋₃ alkylenedioxy, nitro, cyano,optionally halogenated C₁₋ 6 alkyl, optionally halogenated C₃₋₆cycloalkyl, optionally halogenated C₁₋₆ alkoxy, optionally halogenatedC₁₋₆ alkylthio, hydroxyl, amino, mono-C₁₋₆ alkylamino, di-C₁₋₆alkylamino, C₁₋₆ alkyl-carbonylamino, C₁₋₆ alkyl-carbonyl, carboxyl,C₁₋₆ alkoxy-carbonyl, carbamoyl, mono-C₁₋₆ alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, sulfo, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₀aryl and C₆₋₁₀ aryloxy, or ##STR314## wherein ring E is a 5- to10-membered aromatic ring which may be substituted by 1 to 5substituents selected from the group consisting of halogen, C₁₋₃alkylenedioxy, nitro, cyano, optionally halogenated C₁₋ 6 alkyl,optionally halogenated C₃₋₆ cycloalkyl, optionally halogenated C₁₋₆alkoxy, optionally halogenated C₁₋₆ alkylthio, hydroxyl, amino,mono-C₁₋₆ alkylamino, di-C₁₋₆ alkylamino, C₁₋₆ alkyl-carbonylamino, C₁₋₆alkyl-carbonyl, carboxyl, C₁₋₆ alkoxy-carbonyl, carbamoyl, mono-C₁₋₆alkylcarbamoyl, di-C₁₋₆ alkylcarbamoyl, sulfo, C₁₋₆ alkylsulfonyl, C₁₋₆alkylsulfinyl, C₆₋₁₀ aryl and C₆₋₁₀ aryloxy; X is --CH₂ --, --CO-- or--CH(OH)--; Y is --CH₂ --, --O-- or --NW^(b) -- in which W^(b) ishydrogen or a C₁₋₆ alkyl group which may be substituted by 1 to 5substituents selected from the group consisting of halogen, C₁₋₃alkylenedioxy, nitro, cyano, optionally halogenated C₃₋₆ cycloalkyl,optionally halogenated C₁₋₆ alkoxy, optionally halogenated C₁₋₆alkylthio, hydroxyl, amino, mono-C₁₋₆ alkylamino, di-C₁₋₆ alkylamino,C₁₋₆ alkyl-carbonylamino, C₁₋₆ alkyl-carbonyl, carboxyl, C₁₋₆alkoxy-carbonyl, carbamoyl, mono-C₁₋₆ alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, sulfo, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₀aryl, C₆₋₁₀ aryloxy and 5- or 6-membered heterocyclic group; k+m is aninteger of 1 to 4; and n is an integer of 1 to
 3. 3. The compound ofclaim 1 wherein R¹ is a C₇₋₁₆ aralkyl, C₃₋₆ cycloalkyl or benzo-C₃₋₆cycloalkyl group which may be substituted by 1 to 5 substituentsselected from the group consisting of halogen, optionally halogenatedC₁₋₆ alkyl, optionally halogenated C₁₋₆ alkoxy and C₁₋₆ alkoxy-carbonyl.4. The compound of claim 1 wherein R³ is an acyl group of --CO--R^(b)wherein R^(b) is a C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆cycloalkyl, C₆₋₁₄ aryl or C₇₋₁₆ aralkyl group which may be substitutedby 1 to 5 substituents selected from the group consisting of halogen,C₁₋₃ alkylenedioxy, nitro, cyano, optionally halogenated C₃₋₆cycloalkyl, optionally halogenated C₁₋₆ alkoxy, optionally halogenatedC₁₋₆ alkylthio, hydroxyl, amino, mono-C₁₋₆ alkylamino, di-C₁₋₆alkylamino, C₁₋₆ alkyl-carbonylamino, C₁₋₆ alkyl-carbonyl, carboxyl,C₁₋₆ alkoxy-carbonyl, carbamoyl, mono-C₁₋₆ alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, sulfo, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl and 5- or6-membered heterocyclic group.
 5. The compound of claim 1 wherein##STR315## is the formula: ##STR316## wherein ring E^(a) is a benzenering which may be substituted by 1 to 4 substituents selected from thegroup consisting of halogen, C₁₋₃ alkylenedioxy, nitro, cyano,optionally halogenated C₁₋₆ alkyl, optionally halogenated C₃₋₆cycloalkyl, optionally halogenated C₁₋₆ alkoxy, optionally halogenatedC₁₋₆ alkylthio, hydroxyl, amino, mono-C₁₋₆ alkylamino, di-C₁₋₆alkylamino, C₁₋₆ alkyl-carbonylamino, C₁₋₆ alkyl-carbonyl, carboxyl,C₁₋₆ alkoxy-carbonyl, carbamoyl, mono-C₁₋₆ alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, sulfo, C₁₋ 6 alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₆₋₁₀aryl and C₆₋₁₀ aryloxy.
 6. The compound of claim 1 wherein P and Q areindependently a C₂₋₆ alkylene or C₂₋₆ alkenylene group.
 7. The compoundof claim 1 wherein P and Q are independently a C₃₋₅ alkylene group. 8.The compound of claim 1 wherein R⁴ is hydrogen.
 9. The compound of claim1 wherein j is O.
 10. The compound of claim 1 which is the compound ofthe formula: ##STR317## wherein Ar³ and Ar⁴ are independently anoptionally halogenated phenyl group; Alk₁ and Alk₂ are independently aC₂₋₆ alkylene group; Ar⁵ is a C₇₋₁₆ aralkyl group which may besubstituted by halogen or optionally halogenated C₁₋ 3 alkoxy; and ringE^(a) is a benzene ring which may be substituted by 1 to 3 substituentsselected from the group consisting of optionally halogenated C₁₋₃alkoxy, C₁₋₃ alkyl-carbonyl and amino.
 11. The compound of claim 1 whichis(+)-3,4-Dihydro-6-methoxy-1'-{4,4-diphenyl-7-{[(4-methoxyphenyl)acetyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine],(-)-3,4-Dihydro-6-methoxy-1'-{4,4-diphenyl-7-{[(4-methoxyphenyl)acetyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine],(-)-3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-{[(4-methoxyphenyl)acetyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine]-1-one,(-)-3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-{[(4-fluorophenyl)acetyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine],(+)-3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-{[(4-fluorophenyl)acetyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine],(-)-3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-{[3-(4-fluorophenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine],(+)-3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-{[3-(4-fluorophenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine],(+)-3,4-Dihydro-6,7-dimethoxy-1'-{7-{[3-(4-chlorophenyl)propionyl]amino}-4,4-diphenylheptyl}spiro[naphthalene-2(1H),2'-piperidine],(-)-3,4-Dihydro-6,7-dimethoxy-1'-{7-{[3-(4-chlorophenyl)propionyl]amino}-4,4-diphenylheptyl}spiro[naphthalene-2(1H),2'-piperidine],(-)-3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-{[3-(4-methoxyphenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine],(+)-3,4-Dihydro-6,7-dimethoxy-1'-{4,4-diphenyl-7-{[3-(4-methoxyphenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),2'-piperidine], 3.4-Dihydro-4'-{4,4-diphenyl-7-{[3-(4-methoxyphenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),3'-morpholine],3,4-Dihydro-7-methoxy-4'-{4,4-diphenyl-7-{[3-(4-methoxyphenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),3'-morpholine],3,4-Dihydro-6,7-dimethoxy-4'-{4,4-diphenyl-7-{[3-(4-methoxyphenyl)propionyl]amino}heptyl}spiro[naphthalene-2(1H),3'-morpholine], or a salt thereof.
 12. A process forproducing the compound of claim 1, which comprises reacting a compoundof the formula: ##STR318## wherein all symbols are as defined in claim1, or a salt thereof, with a compound of the formula:

    R.sup.4 --L

wherein L represents a leaving group and R⁴ is as defined in claim 1, ora salt thereof.
 13. A gonadotropin-releasing hormone receptorantagonistic composition which comprises a compound of the formula:##STR319## wherein Ar¹ and Ar² independently represent an optionallysubstituted aromatic group;P^(a) and Q^(a) independently represent adivalent aliphatic hydrocarbon group which may have either oxygen orsulfur within the carbon chain; R^(1a) and R^(3a) independentlyrepresent an acyl group or an optionally substituted hydrocarbon group;R² and R⁴ independently represent hydrogen or an optionally substitutedalkyl group; R^(1a) and R² or R^(3a) and R⁴, taken together with theadjacent nitrogen atom, may form an optionally substitutednitrogen-containing heterocyclic group; and j represents 0 or 1, or asalt thereof, and a pharmaceutically acceptable carrier.
 14. Agonadotropin-releasing hormone receptor antagonistic composition whichcomprises the compound of claim 1 or a salt thereof, and apharmaceutically acceptable carrier.
 15. The composition of claim 13which is a composition for treating a sex hormone-dependent disease. 16.The composition of claim 14 which is a composition for treating tumor,prostatic hypertrophy, endometriosis, precocious puberty or premenstrualsyndrome.
 17. A method for treating diseases related togonadotropin-releasing hormone in mammals which comprises the steps ofselecting a compound of the formula: ##STR320## wherein Ar¹ and Ar²independently represent an optionally substituted aromatic group;P^(a)and Q^(a) independently represent a divalent aliphatic hydrocarbon groupwhich may have either oxygen or sulfur within the carbon chain; R^(1a)and R^(3a) independently represent an acyl group or an optionallysubstituted hydrocarbon group; R² and R⁴ independently representhydrogen or an optionally substituted alkyl group; R^(1a) and R² orR^(3a) and R⁴, taken together with the adjacent nitrogen atom, may forman optionally substituted nitrogen-containing heterocyclic group; and jrepresents 0 or 1, or a salt thereof, and administering to a subject atherapeutically effective amount of said compound.
 18. A method ofmanufacturing a pharmaceutical composition for treating diseases relatedto gonadotropin-releasing hormone, comprising the steps of selecting acompound of the formula: ##STR321## wherein Ar¹ and Ar² independentlyrepresent an optionally substituted aromatic group;P^(a) and Q^(a)independently represent a divalent aliphatic hydrocarbon group which mayhave either oxygen or sulfur within the carbon chain; R^(1a) and R^(3a)independently represent an acyl group or an optionally substitutedhydrocarbon group; R² and R⁴ independently represent hydrogen or anoptionally substituted alkyl group; R^(1a) and R² or R^(3a) and R⁴,taken together with the adjacent nitrogen atom, may form an optionallysubstituted nitrogen-containing heterocyclic group; and j represents 0or 1, or a salt thereof; and admixing said compound with apharmaceutically acceptable carrier.